两种蛇毒C-型凝集素的结构生物学研究
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摘要
1.抗血小板药物候选蛋白agkisacucetin的结构研究
心血管疾病是一种严重威胁人类健康的疾病,引起心血管疾病的主要原因是血栓。GP Ⅰ b-Ⅸ-Ⅴ复合物是血小板表面重要的糖蛋白,在血小板粘附的最初阶段,特别是在高切变应力条件下的粘附过程中起着关键作用,因此成为抗血栓药物的重要靶标。agkisacucetin是一种从皖南尖吻蝮蛇蛇毒中分离纯化得到的一种蛇毒C型凝集素,可抑制GP Ⅰ b-VWF相互作用,从而具有抗血栓作用。同时体内实验表明其不易在体内造成凝血障碍,因此是一种新型的抗血栓药物。
本论文对agkisacucetin进行了晶体学研究,最终获得了其1.91A分辨率的晶体结构,为阐明该蛋白抑制GP Ⅰ b-VWF相互作用的分子机制提供了结构基础,同时,通过电子密度图推断的晶体学序列对质谱分析的结果进行了验证和补充。agkisacucetin整体结构与另一个GP Ⅰb结合蛋白flavocetin相似,但其不具有flavocetin或echicetin的多聚机制,因此其与GP Ⅰb的结合抑制GP Ⅰb与VWF的相互作用。
2.抗血管生成素2K001的结构研究
90%的癌症表现为实体瘤,而实体瘤的生长依赖于血管网络为其供应氧气和营养物质。当肿瘤体积超过2～3mm3时,需要形成新血管才能继续生长,否则肿瘤组织将保持休眠状态或发生退化。因此,通过抑制新血管生成来控制肿瘤生长是一种极有希望的抗癌策略。
兆科药业(合肥)有限公司从皖南尖吻蝮蛇蛇毒中分离纯化得到一种蛇毒C型凝集素2K001,在鸡胚绒毛尿囊膜实验中表现为明显的抑制血管生成作用,是一种抗血管生成候选药物。
本论文对抗血管生成素2K001进行了晶体学研究,最终获得了其2.05A分辨率的晶体结构,结合质谱分析结果,确定了其晶体学序列。通过结构比对,发现其一级序列及三维结构都与一个整合素α2βl结合蛋白EMS16非常相似。进一步的实验证实2K001确实可与α2_I-dmain结合。整合素α2β1在新血管生成过程中起着重要作用,2K001可能通过该受体抑制新血管生成。这一发现为进一步阐明其分子机制提供了线索和结构基础。
1. Structural study on agkisacucetin, an anti-GP I b snaclec (snake C-type lectin) from Agkistrodon acutus
Platelet adhesion to a damaged blood vessel is the initial trigger for arterial hemostasis and thrombosis. Agkisacucetin is a snake C-type lectin isolated from the venom of Agkistrodon acutus(A. acutus). It inhibits platelet by binding to GP I b and blocking the access of VWF to GP Ⅰ b. We have determined the crystal structure of agkisacucetin and refined to1.91A. The structure of agkisacucetin shares a very similar (αβ) structure with another GP I b-binding protein flavocetin-A, but without the C-termini cysteine in the β-subunit, agkisacucetin does not form an (αβ)4tetramer or cluster GP I bs like flavocetin-A. An unpaired cysteine in the a-subunit was found being modified to a cysteinesulfonic acid.
2. Structural study on2K001, an anti-angiogenesis snaclec (snake C-type lectin) from Agkistrodon acutus
More than90%of all cancers present as solid tumors which depend on a functioning vascular network to supply oxygen and nutrients. Angiogenesis is the formation of new blood vessels from the pre-existing ones and it is a necessary process in tumors growing. The therapeutic strategy of interfering with angiogenesis holds great promise for cancer therapy.2K001, a snake C-type lectin isolated from the venom of Agkistrodon acutus (A. acutus) by Zhaoke Pharmaceutical (hefei) Co., Ltd., is a potencial anti-angiogenic agent. We have determined the crystal structure of2K001and refined to2.05A.2K001shares a high degree of sequence and structural similarity with EMS16, an integrin α2β1-binding protein. Integrin α2-I-domain was then cloned, expressed and was found to actually interact with2K001. Since integrin β2β1plays key role in angiogenesis,2K001may inhibit angiogenesis by interacting with integrin α2β1. This result provides a clue for the mechanism research on2K001.
心血管疾病是一种严重威胁人类健康的疾病,引起心血管疾病的主要原因是血栓。GP Ⅰ b-Ⅸ-Ⅴ复合物是血小板表面重要的糖蛋白,在血小板粘附的最初阶段,特别是在高切变应力条件下的粘附过程中起着关键作用,因此成为抗血栓药物的重要靶标。agkisacucetin是一种从皖南尖吻蝮蛇蛇毒中分离纯化得到的一种蛇毒C型凝集素,可抑制GP Ⅰ b-VWF相互作用,从而具有抗血栓作用。同时体内实验表明其不易在体内造成凝血障碍,因此是一种新型的抗血栓药物。
本论文对agkisacucetin进行了晶体学研究,最终获得了其1.91A分辨率的晶体结构,为阐明该蛋白抑制GP Ⅰ b-VWF相互作用的分子机制提供了结构基础,同时,通过电子密度图推断的晶体学序列对质谱分析的结果进行了验证和补充。agkisacucetin整体结构与另一个GP Ⅰb结合蛋白flavocetin相似,但其不具有flavocetin或echicetin的多聚机制,因此其与GP Ⅰb的结合抑制GP Ⅰb与VWF的相互作用。
2.抗血管生成素2K001的结构研究
90%的癌症表现为实体瘤,而实体瘤的生长依赖于血管网络为其供应氧气和营养物质。当肿瘤体积超过2～3mm3时,需要形成新血管才能继续生长,否则肿瘤组织将保持休眠状态或发生退化。因此,通过抑制新血管生成来控制肿瘤生长是一种极有希望的抗癌策略。
兆科药业(合肥)有限公司从皖南尖吻蝮蛇蛇毒中分离纯化得到一种蛇毒C型凝集素2K001,在鸡胚绒毛尿囊膜实验中表现为明显的抑制血管生成作用,是一种抗血管生成候选药物。
本论文对抗血管生成素2K001进行了晶体学研究,最终获得了其2.05A分辨率的晶体结构,结合质谱分析结果,确定了其晶体学序列。通过结构比对,发现其一级序列及三维结构都与一个整合素α2βl结合蛋白EMS16非常相似。进一步的实验证实2K001确实可与α2_I-dmain结合。整合素α2β1在新血管生成过程中起着重要作用,2K001可能通过该受体抑制新血管生成。这一发现为进一步阐明其分子机制提供了线索和结构基础。
1. Structural study on agkisacucetin, an anti-GP I b snaclec (snake C-type lectin) from Agkistrodon acutus
Platelet adhesion to a damaged blood vessel is the initial trigger for arterial hemostasis and thrombosis. Agkisacucetin is a snake C-type lectin isolated from the venom of Agkistrodon acutus(A. acutus). It inhibits platelet by binding to GP I b and blocking the access of VWF to GP Ⅰ b. We have determined the crystal structure of agkisacucetin and refined to1.91A. The structure of agkisacucetin shares a very similar (αβ) structure with another GP I b-binding protein flavocetin-A, but without the C-termini cysteine in the β-subunit, agkisacucetin does not form an (αβ)4tetramer or cluster GP I bs like flavocetin-A. An unpaired cysteine in the a-subunit was found being modified to a cysteinesulfonic acid.
2. Structural study on2K001, an anti-angiogenesis snaclec (snake C-type lectin) from Agkistrodon acutus
More than90%of all cancers present as solid tumors which depend on a functioning vascular network to supply oxygen and nutrients. Angiogenesis is the formation of new blood vessels from the pre-existing ones and it is a necessary process in tumors growing. The therapeutic strategy of interfering with angiogenesis holds great promise for cancer therapy.2K001, a snake C-type lectin isolated from the venom of Agkistrodon acutus (A. acutus) by Zhaoke Pharmaceutical (hefei) Co., Ltd., is a potencial anti-angiogenic agent. We have determined the crystal structure of2K001and refined to2.05A.2K001shares a high degree of sequence and structural similarity with EMS16, an integrin α2β1-binding protein. Integrin α2-I-domain was then cloned, expressed and was found to actually interact with2K001. Since integrin β2β1plays key role in angiogenesis,2K001may inhibit angiogenesis by interacting with integrin α2β1. This result provides a clue for the mechanism research on2K001.
引文
Adams, P. D., P. V. Afonine, et al. (2010). "PHENIX:a comprehensive Python-based system for macromolecular structure solution." Acta Crystallogr D Biol Crystallogr 66(Pt 2):213-221.
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Batuwangala, T., M. Leduc, et al. (2004). "Structure of the snake-venom toxin convulxin." Acta Crystallogr D Biol Crystallogr 60(Pt 1):46-53.
Bergmeier, W., D. Bouvard, et al. (2001). "Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha." J Biol Chem 276(27):25121-25126.
Bergmeier, W., C. L. Piffath, et al. (2006). "The role of platelet adhesion receptor GP I balpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis." Proc Natl Acad Sci U S A 103(45):16900-16905.
Chang, C. H., C. H. Chung, et al. (2008). "The highly specific platelet glycoprotein (GP) VI agonist trowaglerix impaired collagen-induced platelet aggregation ex vivo through matrix metalloproteinase-dependent GPVI shedding." J Thromb Haemost 6(4):669-676.
Chen, V. B., W. B. Arendall,3rd, et al. (2010). "MolProbity:all-atom structure validation for macromolecular crystallography." Acta Crystallogr D Biol Crystallogr 66(Pt 1):12-21.
Chung, C. H., L. C. Au, et al. (1999). "Molecular cloning and sequence analysis of aggretin, a collagen-like platelet aggregation inducer." Biochem Biophys Res Commun 263(3):723-727.
Clemetson, K. J. (2010). "Snaclecs (snake C-type lectins) that inhibit or activate platelets by binding to receptors." Toxicon 56(7):1236-1246.
Clemetson, K. J., T. Morita, et al. (2009). "Scientific and standardization committee communications:classification and nomenclature of snake venom C-type lectins and related proteins." J Thromb Haemost 7(2):360.
Coller, B. S., E. I. Peerschke, et al. (1983). "A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins Ⅱb and/or Ⅲa." J Clin Invest 72(1):325-338.
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Andrews, R. K. and M. C. Berndt (2004). "Platelet physiology and thrombosis." Thromb Res 114(5-6):447-453.
Batuwangala, T., M. Leduc, et al. (2004). "Structure of the snake-venom toxin convulxin." Acta Crystallogr D Biol Crystallogr 60(Pt 1):46-53.
Bergmeier, W., D. Bouvard, et al. (2001). "Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha." J Biol Chem 276(27):25121-25126.
Bergmeier, W., C. L. Piffath, et al. (2006). "The role of platelet adhesion receptor GP I balpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis." Proc Natl Acad Sci U S A 103(45):16900-16905.
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Chen, V. B., W. B. Arendall,3rd, et al. (2010). "MolProbity:all-atom structure validation for macromolecular crystallography." Acta Crystallogr D Biol Crystallogr 66(Pt 1):12-21.
Chung, C. H., L. C. Au, et al. (1999). "Molecular cloning and sequence analysis of aggretin, a collagen-like platelet aggregation inducer." Biochem Biophys Res Commun 263(3):723-727.
Clemetson, K. J. (2010). "Snaclecs (snake C-type lectins) that inhibit or activate platelets by binding to receptors." Toxicon 56(7):1236-1246.
Clemetson, K. J., T. Morita, et al. (2009). "Scientific and standardization committee communications:classification and nomenclature of snake venom C-type lectins and related proteins." J Thromb Haemost 7(2):360.
Coller, B. S., E.I. Peerschke, et al. (1983). "A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins Ⅱb and/or Ⅲa." J Clin Invest 72(1):325-338.
de Vries, S. J., M. van Dijk, et al. (2010). "The HADDOCK web server for data-driven biomolecular docking." Nat Protoc 5(5):883-897.
Dodd, R. B. and K. Drickamer (2001). "Lectin-like proteins in model organisms:implications for evolution of carbohydrate-binding activity." Glycobiology 11(5):71R-79R.
Drickamer, K. and M. E. Taylor (1993). "Biology of animal lectins." Annu Rev Cell Biol 9: 237-264.
Du, X. Y., J. M. Clemetson, et al. (2002). "Ophioluxin, a convulxin-like C-type lectin from Ophiophagus hannah (King cobra) is a powerful platelet activator via glycoprotein Ⅵ." J Biol Chem 277(38):35124-35132.
Dubois, C., L. Panicot-Dubois, et al. (2006). "Glycoprotein Ⅵ-dependent and -independent pathways of thrombus formation in vivo." Blood 107(10):3902-3906.
Dumas, J. J., R. Kumar, et al. (2004). "Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations." J Biol Chem 279(22):23327-23334.
Dumas, J. J., R. Kumar, et al. (2003). "Crystal structure of the GP I balpha-thrombin complex essential for platelet aggregation." Science 301(5630):222-226.
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Eble, J. A., S. Niland, et al. (2009). "The alpha2betal integrin-specific antagonist rhodocetin is a cruciform, heterotetrameric molecule." FASEB J 23(9):2917-2927.
Emsley, P. and K. Cowtan (2004). "Coot:model-building tools for molecular graphics." Acta Crystallographica Section D-Biological Crystallography 60:2126-2132.
Fukuda, K., T. Doggett, et al. (2005). "The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation." Nat Struct Mol Biol 12(2):152-159.
Fukuda, K., T. A. Doggett, et al. (2002). "Structural basis of von Willebrand factor activation by the snake toxin botrocetin." Structure 10(7):943-950.
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Hooley, E., E. Papagrigoriou, et al. (2008), "The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure." Biochemistry 47(30):7831-7837.
Horii, K., M. T. Brooks, et al. (2009). "Convulxin forms a dimer in solution and can bind eight copies of glycoprotein Ⅵ:implications for platelet activation." Biochemistry 48(13): 2907-2914.
Horii, K.., D. Okuda, et al. (2004). "Crystal structure of EMS 16 in complex with the integrin alpha2-I domain." J Mol Biol 341 (2):519-527.
Huizinga, E. G., S. Tsuji, et al. (2002). "Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain." Science 297(5584):1176-1179.
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Jasti, J., M. Paramasivam, et al. (2004). "Crystal structure of echicetin from Echis carinatus (Indian saw-scaled viper) at 2.4A resolution." J Mol Biol 335(11:167-176.
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Kunita, A., T. G. Kashima, et al. (2007). "The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis." Am J Pathol 170(4):1337-1347.
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Paaventhan, P., C. Kong, et al. (2005). "Structure of rhodocetin reveals noncovalently bound heterodimer interface." Protein Sci 14(1):169-175.
Painter, J. and E. A. Merritt (2006). "Optimal description of a protein structure in terms of multiple groups undergoing TLS motion." Acta Crystallogr D Biol Crystallogr 62(Pt 4):439-450.
Peng, M., J. C. Holt, et al. (1994). "Isolation, characterization and amino acid sequence of echicetin beta subunit, a specific inhibitor of von Willebrand factor and thrombin interaction with glycoprotein Ⅰb." Biochem Biophys Res Commun 205(1):68-72.
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Read, M. S., J. Y. Potter, et al. (1983). "Venom coagglutinin for detection of von Willebrand factor activity in animal plasmas." J Lab Clin Med 101(1):74-82.
Read, M. S., R. W. Shermer, et al. (1978). "Venom coagglutinin:an activator of platelet aggregation dependent on von Willebrand factor." Proc Natl Acad Sci U S A 75(9): 4514-4518.
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Siljander, P. R., I. C. Munnix, et al. (2004). "Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood." Blood 103(4):1333-1341.
Staniszewska, I., E. M. Walsh, et al. (2009). "Effect of VP12 and viperistatin on inhibition of collagen-receptor-dependent melanoma metastasis." Cancer Biol Ther 8(15):1507-1516.
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Watson, A. A., J. A. Eble, et al. (2008). "Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2." Protein Sci 17(9):1611-1616.
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Batuwangala, T., M. Leduc, et al. (2004). "Structure of the snake-venom toxin convulxin." Acta Crystallogr D Biol Crystallogr 60(Pt 1):46-53.
Bergmeier, W., D. Bouvard, et al. (2001). "Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha." J Biol Chem 276(27):25121-25126.
Bergmeier, W., C. L. Piffath, et al. (2006). "The role of platelet adhesion receptor GP I balpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis." Proc Natl Acad Sci U S A 103(45):16900-16905.
Chang, C. H., C. H. Chung, et al. (2008). "The highly specific platelet glycoprotein (GP) VI agonist trowaglerix impaired collagen-induced platelet aggregation ex vivo through matrix metalloproteinase-dependent GPVI shedding." J Thromb Haemost 6(4):669-676.
Chen, V. B., W. B. Arendall,3rd, et al. (2010). "MolProbity:all-atom structure validation for macromolecular crystallography." Acta Crystallogr D Biol Crystallogr 66(Pt 1):12-21.
Chung, C. H., L. C. Au, et al. (1999). "Molecular cloning and sequence analysis of aggretin, a collagen-like platelet aggregation inducer." Biochem Biophys Res Commun 263(3):723-727.
Clemetson, K. J. (2010). "Snaclecs (snake C-type lectins) that inhibit or activate platelets by binding to receptors." Toxicon 56(7):1236-1246.
Clemetson, K. J., T. Morita, et al. (2009). "Scientific and standardization committee communications:classification and nomenclature of snake venom C-type lectins and related proteins." J Thromb Haemost 7(2):360.
Coller, B. S., E. I. Peerschke, et al. (1983). "A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins Ⅱb and/or Ⅲa." J Clin Invest 72(1):325-338.
de Vries, S. J., M. van Dijk, et al. (2010). "The HADDOCK web server for data-driven biomolecular docking." Nat Protoc 5(5):883-897.
Dodd, R. B. and K. Drickamer (2001). "Lectin-like proteins in model organisms:implications for evolution of carbohydrate-binding activity." Glycobiology 11(5):71R-79R.
Drickamer, K. and M. E. Taylor (1993). "Biology of animal lectins." Annu Rev Cell Biol 9: 237-264.
Du, X. Y., J. M. Clemetson, et al. (2002). "Ophioluxin, a convulxin-like C-type lectin from Ophiophagus hannah (King cobra) is a powerful platelet activator via glycoprotein Ⅵ." J Biol Chem 277(38):35124-35132.
Dubois, C., L. Panicot-Dubois, et al. (2006). "Glycoprotein Ⅵ-dependent and-independent pathways of thrombus formation in vivo." Blood 107(10):3902-3906.
Dumas, J. J., R. Kumar, et al. (2004). "Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations." J Biol Chem 279(22):23327-23334.
Dumas, J. J., R. Kumar, et al. (2003). "Crystal structure of the GP Ⅰ balpha-thrombin complex essential for platelet aggregation." Science 301(5630):222-226.
Eble, J. A., S. Niland, et al. (2009). "The alpha2betal integrin-specific antagonist rhodocetin is a cruciform, heterotetrameric molecule." FASEB J 23(9):2917-2927.
Emsley, P. and K. Cowtan (2004). "Coot:model-building tools for molecular graphics." Acta Crystal lographica Section D-Biological Crystallography 60:2126-2132.
Fukuda, K., T. Doggett, et al. (2005). "The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation." Nat Struct Mol Biol 12(2):152-159.
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Harrison, P. (2005). "Platelet function analysis." Blood Rev 19(2):111-123.
Hooley, E., E. Papagrigoriou, et al. (2008). "The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure." Biochemistry 47(30):7831-7837.
Horii, K., M. T. Brooks, et al. (2009). "Convulxin forms a dimer in solution and can bind eight copies of glycoprotein VI:implications for platelet activation." Biochemistry 48(13): 2907-2914.
Horii, K., D. Okuda, et al. (2004). "Crystal structure of EMS 16 in complex with the integrin alpha2-1 domain." J Mol Biol 341(2):519-527.
Huizinga, E. G., S. Tsuji, et al. (2002). "Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain." Science 297(5584):1176-1179.
Jandrot-Perrus, M., A. H. Lagrue, et al. (1997). "Adhesion and activation of human platelets induced by convulxin involve glycoprotein VI and integrin alpha2betal." J Biol Chem 272(43):27035-27041.
Jasti, J., M. Paramasivam, et al. (2004). "Crystal structure of echicetin from Echis carinatus (Indian saw-scaled viper) at 2.4A resolution." J Mol Biol 335(1):167-176.
Kanaji, S., T. Kanaji, et al. (2003). "Convulxin binds to native, human glycoprotein Ⅰb alpha." J Biol Chem 278(41):39452-39460.
Kato, Y., M. K. Kaneko, et al. (2008). "Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2." Cancer Sci 99(1):54-61.
Kerrigan, A. M., K. M. Dennehy, et al. (2009). "CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils." J Immunol 182(7):4150-4157.
Kleywegt, G. J. (2007). "Crystallographic refinement of ligand complexes." Acta Crystallogr D Biol Crystallogr 63(Pt 1):94-100.
Kunita, A., T. G. Kashima, et al. (2007). "The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis." Am J Pathol 170(4):1337-1347.
Laskowski, R., M. Mac Arthur, et al. (1993). "PROCHECK:A program to check the stereochemical quality of protein structures " J. Appl. Cryst.26:283-291.
Lee, W. H., X. Y. Du, et al. (2003). "Stejnulxin, a novel snake C-type lectin-like protein from Trimeresurus stejnegeri venom is a potent platelet agonist acting specifically via GPVI." Thromb Haemost 90(4):662-671.
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Lopez, J. A. (1994). "The platelet glycoprotein Ⅰb-Ⅸ complex." Blood Coagul Fibrinolysis 5(1): 97-119.
Maita, N., K. Nishio, et al. (2003). "Crystal structure of von Willebrand factor A1 domain complexed with snake venom, bitiscetin:insight into glycoprotein lbalpha binding mechanism induced by snake venom proteins." J Biol Chem 278(39):37777-37781.
Miner, J. and A. Hoffhines (2007). "The discovery of aspirin's antithrombotic effects." Tex Heart Inst J 34(2):179-186.
Murakami, M. T., S. P. Zela, et al. (2003). "Crystal structure of the platelet activator convulxin, a disulfide-linked alpha4beta4 cyclic tetramer from the venom of Crotalus durissus terrificus.1 Biochem Biophys Res Commun 310(2):478-482.
Navdaev, A., D. Dormann, et al. (2001). "Echicetin, a GP I b-binding snake C-type lectin from Echis carinatus, also contains a binding site for IgMkappa responsible for platelet agglutination in plasma and inducing signal transduction." Blood 97(8):2333-2341.
Paaventhan, P., C. Kong, et al. (2005). "Structure of rhodocetin reveals noncovalently bound heterodimer interface." Protein Sci 14(1):169-175.
Painter, J. and E. A. Merritt (2006). "Optimal description of a protein structure in terms of multiple groups undergoing TLS motion." Acta Crystallogr D Biol Crystallogr 62(Pt 4):439-450.
Peng, M., J. C. Holt, et al. (1994). "Isolation, characterization and amino acid sequence of echicetin beta subunit, a specific inhibitor of von Willebrand factor and thrombin interaction with glycoprotein Ⅰb." Biochem Biophys Res Commun 205(1):68-72.
Peng, M., W. Lu, et al. (1993). "Echicetin:a snake venom protein that inhibits binding of von Willebrand factor and alboaggregins to platelet glycoprotein Ⅰb." Blood 81(9):2321-2328.
Polgar, J., J. M. Clemetson, et al. (1997). "Platelet activation and signal transduction by convulxin, a C-type lectin from Crotalus durissus terrificus (tropical rattlesnake) venom via the p62/GPVI collagen receptor." J Biol Chem 272(21):13576-13583.
Read, M. S., J. Y. Potter, et al. (1983). "Venom coagglutinin for detection of von Willebrand factor activity in animal plasmas." J Lab Clin Med 101(1):74-82.
Read, M. S., R. W. Shermer, et al. (1978). "Venom coagglutinin:an activator of platelet aggregation dependent on von Willebrand factor." Proc Natl Acad Sci U S A 75(9): 4514-4518.
Sarratt, K. L., H. Chen, et al. (2005). "GPVI and alpha2betal play independent critical roles during platelet adhesion and aggregate formation to collagen under flow." Blood 106(4): 1268-1277.
Schuttelkopf, A. W. and D. M. van Aalten (2004). "PRODRG:a tool for high-throughput crystallography of protein-ligand complexes." Acta Crystallogr D Biol Crystallogr 60(Pt 8): 1355-1363.
Siljander, P. R., I. C. Munnix, et al. (2004). "Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood." Blood 103(4):1333-1341.
Staniszewska, I., E. M. Walsh, et al. (2009). "Effect of VP12 and viperistatin on inhibition of collagen-receptor-dependent melanoma metastasis." Cancer Biol Ther 8(15):1507-1516.
Suzuki-Inoue, K., G. L. Fuller, et al. (2006). "A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2." Blood 107(2):542-549.
Vanhoorelbeke, K., H. Ulrichts, et al. (2003). "Inhibition of platelet adhesion to collagen as a new target for antithrombotic drugs." Curr Drug Targets Cardiovasc Haematol Disord 3(2): 125-140.
Wang, R., R. M. Kini, et al. (1999). "Rhodocetin, a novel platelet aggregation inhibitor from the venom of Calloselasma rhodostoma (Malayan pit viper):synergistic and noncovalent interaction between its subunits." Biochemistry 38(23):7584-7593.
Watson, A. A., J. A. Eble, et al. (2008). "Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2." Protein Sci 17(9):1611-1616.
Winn, M. D., G. N. Murshudov, et al. (2003). "Macromolecular TLS refinement in REFMAC at moderate resolutions." Methods Enzymol 374:300-321.
Adams, P. D., P. V. Afonine, et al. (2010). "PHENIX:a comprehensive Python-based system for macromolecular structure solution." Acta Crystallogr D Biol Crystallogr 66(Pt 2):213-221.
Andrews, R. K. and M. C. Berndt (2004). "Platelet physiology and thrombosis." Thromb Res 114(5-6):447-453.
Batuwangala, T., M. Leduc, et al. (2004). "Structure of the snake-venom toxin convulxin." Acta Crystallogr D Biol Crystallogr 60(Pt 1):46-53.
Bergmeier, W., D. Bouvard, et al. (2001). "Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha." J Biol Chem 276(27):25121-25126.
Bergmeier, W., C. L. Piffath, et al. (2006). "The role of platelet adhesion receptor GP I balpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis." Proc Natl Acad Sci U S A 103(45):16900-16905.
Bix G., Fu J., et al. (2004)."Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2betal integrin" J. Cell Biol.166:97-109.
Chang, C. H., C. H. Chung, et al. (2008). "The highly specific platelet glycoprotein (GP) VI agonist trowaglerix impaired collagen-induced platelet aggregation ex vivo through matrix metalloproteinase-dependent GPVI shedding." J Thromb Haemost 6(4):669-676.
Chen, V. B., W. B. Arendall,3rd, et al. (2010). "MolProbity:all-atom structure validation for macromolecular crystallography." Acta Crystallogr D Biol Crystallogr 66(Pt 1):12-21.
Chung, C. H., L. C. Au, et al. (1999). "Molecular cloning and sequence analysis of aggretin, a collagen-like platelet aggregation inducer." Biochem Biophys Res Commun 263(3):723-727.
Clemetson, K. J. (2010). "Snaclecs (snake C-type lectins) that inhibit or activate platelets by binding to receptors." Toxicon 56(7):1236-1246.
Clemetson, K. J., T. Morita, et al. (2009). "Scientific and standardization committee communications:classification and nomenclature of snake venom C-type lectins and related proteins." J Thromb Haemost 7(2):360.
Coller, B. S., E.I. Peerschke, et al. (1983). "A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins Ⅱb and/or Ⅲa." J Clin Invest 72(1):325-338.
de Vries, S. J., M. van Dijk, et al. (2010). "The HADDOCK web server for data-driven biomolecular docking." Nat Protoc 5(5):883-897.
Dodd, R. B. and K. Drickamer (2001). "Lectin-like proteins in model organisms:implications for evolution of carbohydrate-binding activity." Glycobiology 11(5):71R-79R.
Drickamer, K. and M. E. Taylor (1993). "Biology of animal lectins." Annu Rev Cell Biol 9: 237-264.
Du, X. Y., J. M. Clemetson, et al. (2002). "Ophioluxin, a convulxin-like C-type lectin from Ophiophagus hannah (King cobra) is a powerful platelet activator via glycoprotein Ⅵ." J Biol Chem 277(38):35124-35132.
Dubois, C., L. Panicot-Dubois, et al. (2006). "Glycoprotein Ⅵ-dependent and -independent pathways of thrombus formation in vivo." Blood 107(10):3902-3906.
Dumas, J. J., R. Kumar, et al. (2004). "Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations." J Biol Chem 279(22):23327-23334.
Dumas, J. J., R. Kumar, et al. (2003). "Crystal structure of the GP I balpha-thrombin complex essential for platelet aggregation." Science 301(5630):222-226.
Eble, J. A, (2005) "Collagen-binding integrins as pharmaceutical targets." Curr. Pharm. Des.11 867-880.
Eble, J. A., S. Niland, et al. (2009). "The alpha2betal integrin-specific antagonist rhodocetin is a cruciform, heterotetrameric molecule." FASEB J 23(9):2917-2927.
Emsley, P. and K. Cowtan (2004). "Coot:model-building tools for molecular graphics." Acta Crystallographica Section D-Biological Crystallography 60:2126-2132.
Fukuda, K., T. Doggett, et al. (2005). "The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation." Nat Struct Mol Biol 12(2):152-159.
Fukuda, K., T. A. Doggett, et al. (2002). "Structural basis of von Willebrand factor activation by the snake toxin botrocetin." Structure 10(7):943-950.
Gaurnier-Hausser A, Rothman VL, et al. (2008). "The novel angiogenic inhibitor, angiocidin, induces differentiation of monocytes to macrophages." Cancer Res. Jul 15;68(14):5905-14.
Griffioen, A. W. and G. Molema (2000). "Angiogenesis:potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation." Pharmacol Rev 52(2):237-268.
Harrison, P. (2005). "Platelet function analysis." Blood Rev 19(2):111-123.
Hooley, E., E. Papagrigoriou, et al. (2008), "The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure." Biochemistry 47(30):7831-7837.
Horii, K., M. T. Brooks, et al. (2009). "Convulxin forms a dimer in solution and can bind eight copies of glycoprotein Ⅵ:implications for platelet activation." Biochemistry 48(13): 2907-2914.
Horii, K.., D. Okuda, et al. (2004). "Crystal structure of EMS 16 in complex with the integrin alpha2-I domain." J Mol Biol 341 (2):519-527.
Huizinga, E. G., S. Tsuji, et al. (2002). "Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain." Science 297(5584):1176-1179.
Ignoffo, R. J. (2004). "Overview of bevacizumab:a new cancer therapeutic strategy targeting vascular endothelial growth factor." Am J Health Syst Pharm 61(21 Suppl 5):S21-26.
Izumi, Y., L. Xu, et al. (2002). "Tumour biology:herceptin acts as an anti-angiogenic cocktail." Nature 416(6878):279-280.
Jandrot-Perrus, M., A. H. Lagrue, et al. (1997). "Adhesion and activation of human platelets induced by convulxin involve glycoprotein VI and integrin alpha2betal." J Biol Chem 272(43):27035-27041.
Jasti, J., M. Paramasivam, et al. (2004). "Crystal structure of echicetin from Echis carinatus (Indian saw-scaled viper) at 2.4A resolution." J Mol Biol 335(11:167-176.
Kalluri R. (2003). Basement membranes:structure, assembly and role in tumor angiogenesis. Nat Rev Cancer,3:422-433
Kanaji, S., T. Kanaji, et al. (2003). "Convulxin binds to native, human glycoprotein Ib alpha." J Biol Chem 278(41):39452-39460.
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