Structural signatures of DRD4 mutants revealed using molecular dynamics simulations: Implications for drug targeting

详细信息    查看全文

• 作者：Nidhi Jatana ; Lipi Thukral ; N. Latha
• 关键词：GPCR ; Ligand binding ; Molecular dynamics simulations ; Mutations ; Intra ; protein network
• 刊名：Journal of Molecular Modeling
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：22
• 期：1
• 全文大小：3,530 KB
• 参考文献：1.Li Y, Hou T, Goddard I (2010) Computational modeling of structure-function of G protein-coupled receptors with applications for drug design. Current Medicinal Chemistry 17:1167鈥?180CrossRef
  2.Juyal RC, Das M, Punia S, Behari M, Nainwal G, et al. (2006) Genetic susceptibility to Parkinson鈥檚 disease among south and north Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120-bp duplication marker. Neurogenetics 7:223鈥?29CrossRef
  3.Seeman P, Guan HC, Van Tol HH (1993) Dopamine D4 receptors elevated in schizophrenia. Nature 365:441鈥?45CrossRef
  4.Pritchard AL, Ratcliffe L, Sorour E, Haque S, Holder R, et al. (2009) Investigation of dopamine receptors in susceptibility to behavioural and psychological symptoms in Alzheimer鈥檚 disease. International Journal of Geriatric Psychiatry 24:1020鈥?025CrossRef
  5.Pavese N, Andrews TC, Brooks DJ, Ho AK, Rosser AE, et al. (2003) Progressive striatal and cortical dopamine receptor dysfunction in Huntington鈥檚 disease: a PET study. Brain 126:1127鈥?135CrossRef
  6.Probst WC, Snyder LA, Schuster DI, Brosius J, Sealfon SC (1992) Sequence alignment of the G protein-coupled receptor superfamily. DNA and Cell Biology 11:1鈥?0CrossRef
  7.Tuteja N (2009) Signaling through G protein coupled receptors. Plant Signaling & Behavior 4:942鈥?47CrossRef
  8.Chien EY, Liu W, Zhao Q, Katritch V, Han GW, et al. (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330:1091鈥?095CrossRef
  9.Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiological Reviews 78:189鈥?25
  10.Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological Reviews 63:182鈥?17CrossRef
  11.Jatana N, Thukral L, Latha N (2015) Structure and dynamics of DRD4 bound to an agonist and an antagonist using in silico approaches. Proteins: Structure, Function, and Bioinformatics 83:867鈥?80CrossRef
  12.Shaikh S, Collier D, Sham P, Pilowsky L, Sharma T, et al. (1995) Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. American Journal of Medical Genetics 60:541鈥?45CrossRef
  13.Wong AH, Buckle CE, Van Tol HH (2000) Polymorphisms in dopamine receptors: what do they tell us? European Journal of Pharmaceutics and Biopharmaceutics 410:183鈥?03
  14.Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, et al. (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358:149鈥?52CrossRef
  15.Ding YC, Chi HC, Grady DL, Morishima A, Kidd JR, et al. (2002) Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proceedings of the National Academy of Sciences 99:309鈥?14CrossRef
  16.Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK (1996) The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Human Genetics 98:91鈥?01CrossRef
  17.Wang E, Ding YC, Flodman P, Kidd J, Kidd K, et al. (2004) The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. American Journal of Human Genetics 74:931鈥?44CrossRef
  18.Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, et al. (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. Journal of Neurochemistry 65:1157鈥?165CrossRef
  19.Liu I, Seeman P, Sanyal S, Ulpian C, Rodgers-Johnson PE (1996) Dopamine D4 receptor variant in Africans D4valinel94glycine, is insensitive to dopamine and clozapine: report of a homozygous individual. American Journal of Medical Genetics 61:277鈥?82CrossRef
  20.Seeman P, Ulpian C, Chouinard G, Van Tol H, Dwosh H, et al. (1994) Dopamine D4 receptor variant, D4 glycine194, in Africans, but not in Caucasians: no association with schizophrenia. American Journal of Medical Genetics 54:384鈥?90CrossRef
  21.Michealraj K, Jatana N, Jafurulla M, Narayanan L, Chattopadhyay A, et al. (2014) Functional characterization of rare variants in human dopamine receptor D4 gene by genotype鈥損henotype correlations. Neuroscience 262:176鈥?89CrossRef
  22.Eswar N, Webb B, Marti-Renom MA, Madhusudhan M, Eramian D, et al. (2006) Comparative protein structure modeling using modeller. Current Protocols in Bioinformatics Chapter 5: Unit 5:6
  23.Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) Novel procedure for modeling ligand/receptor induced fit effects. Journal of Medicinal Chemistry 49:534鈥?53CrossRef
  24.Schr枚dinger S (2012) Induced fit docking protocol; glide version 5.8, prime version 3.1. Schr枚dinger, LLC, New York
  25.Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design 27:221鈥?34CrossRef
  26.LigPrep (2012) Version 2.5,. Schr枚dinger. LLC, New York
  27.Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, et al. (2006) Scalable algorithms for molecular dynamics simulations on commodity clusters. In: SC 2006 Conference, Proceedings of the ACM/IEEE, IEEE, pp 43鈥?3
  28.Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. Journal of the American Chemical Society 118:11225鈥?1236CrossRef
  29.Jorgensen WL, Madura JD (1985) Temperature and size dependence for Monte Carlo simulations of TIP4P water. Molecular Physics 56:1381鈥?392CrossRef
  30.Liu DC, Nocedal J (1989) On the limited memory BFGS method for large-scale optimization. Math Program 45:503鈥?28CrossRef
  31.Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. The Journal of Chemical Physics 81:3684鈥?690CrossRef
  32.Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An n log (n) method for Ewald sums in large systems. The Journal of Chemical Physics 98:10089鈥?0092CrossRef
  33.Doncheva NT, Klein K, Domingues FS, Albrecht M (2011) Analyzing and visualizing residue networks of protein structures. Trends in Biochemical Sciences 36:179鈥?82CrossRef
  34.Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, et al. (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Research 13:2498鈥?504CrossRef
  35.DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San Carlos
  36.Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. Journal of Molecular Graphics 14:33鈥?8CrossRef
  37.Maestro (2012) Version 9.3, schr枚dinger, llc. New York
  38.Allain A, de Beauch锚ne IC, Langenfeld F, Guarracino Y, Laine E, et al. (2014) Allosteric pathway identification through network analysis: from molecular dynamics simulations to interactive 2D and 3D graphs. Faraday Discussions 169:303鈥?321CrossRef
  39.Case D, Darden T, Cheatham III T, Simmerling C, Wang J, et al. (2012) Amber 13. University of California, San Francisco
  40.Chennubhotla C, Bahar I (2007) Signal propagation in proteins and relation to equilibrium fluctuations. PLoS Computational Biology 3:1716鈥?726
  41.Wallace AC, Laskowski RA, Thornton JM (1995) Ligplot: a program to generate schematic diagrams of protein鈥搇igand interactions. Protein Engineering 8:127鈥?34CrossRef
  42.Bastian M, Heymann S, Jacomy M, et al. (2009) Gephi: an open source software for exploring and manipulating networks. ICWSM 8:361鈥?62
  43.Hayes JM, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J, et al. (2011) Kinetics, in silico docking, molecular dynamics, and mm-gbsa binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined. Proteins: Structure, Function, and Bioinformatics 79:703鈥?19CrossRef
  44.Adasme-Carre帽o F, Mu帽oz-Gutierrez C, Caballero J, Alzate-Morales JH (2014) Performance of the MM/GBSA scoring using a binding site hydrogen bond network-based frame selection: the protein kinase case. Physical Chemistry Chemical Physics 16:14047鈥?4058CrossRef
  45.Prime (2012) Version 3.1, schr枚dinger, llc. version 31, Schr枚dinger. LLC, New York
  46.Li J, Abel R, Zhu K, Cao Y, Zhao S, et al. (2011) The vsgb 2.0 model: a next-generation energy model for high-resolution protein structure modeling. Proteins: Structure, Function, and Bioinformatics 79:2794鈥?812CrossRef
  47.Rastelli G, Rio AD, Degliesposti G, Sgobba M (2010) Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA. Journal of Computational Chemistry 31:797鈥?810
  48.Berezin C, Glaser F, Rosenberg J, Paz I, Pupko T, et al. (2004) Conseq: the identification of functionally and structurally important residues in protein sequences. Bioinformatics 20:1322鈥?324CrossRef
  49.Celniker G, Nimrod G, Ashkenazy H, Glaser F, Martz E, et al. (2013) Consurf: using evolutionary data to raise testable hypotheses about protein function. Israel Journal of Chemistry 53:199鈥?06CrossRef
  50.Venkatakrishnan A, Deupi X, Lebon G, Tate CG, Schertler GF, et al. (2013) Molecular signatures of G-protein-coupled receptors. Nature 494:185鈥?94CrossRef
  51.Feng Z, Hou T, Li Y (2012) Selectivity and activation of dopamine D3R from molecular dynamics. Journal of Molecular Modeling 18:5051鈥?063CrossRef
  52.Oak JN, Oldenhof J, Van Tol HH (2000) The dopamine d(4) receptor: one decade of research. European Journal of Pharmacology: Molecular Pharmacology 405:303鈥?327CrossRef
  53.Kalani MYS, Vaidehi N, Hall SE, Trabanino RJ, Freddolino PL, et al. (2004) The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. In: Proceedings of the National Academy of Sciences of the United States of America, vol 101, pp 3815鈥?3820
  54.Kling RC, Lanig H, Clark T, Gmeiner P (2013) Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling. PloS one 8:e67244CrossRef
  55.Goddard WA, Abrol R (2007) 3-dimensional structures of G protein-coupled receptors and binding sites of agonists and antagonists. The Journal of Nutrition 137:1528S鈥?538S
  56.Chemel BR, Bonner LA, Watts VJ, Nichols DE (2012) Ligand-specific roles for transmembrane 5 serine residues in the binding and efficacy of dopamine D1 receptor catechol agonists. Molecular Pharmacology 81:729鈥?38CrossRef
  57.Schmidt WJ, Reith ME (2005) Dopamine and glutamate in psychiatric disorders. Springer
  58.Jacobson KA, Costanzi S, Paoletta S (2014) Computational studies to predict or explain G protein-coupled receptor polypharmacology. Trends in Pharmacological Sciences 35:658鈥?663CrossRef
  59.Ballesteros JA, Weinstein H (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure鈥揻unction relations in G protein-coupled receptors. Methods in Neurosciences 25:366鈥?28CrossRef
  60.Laine E, Auclair C, Tchertanov L (2012) Allosteric communication across the native and mutated kit receptor tyrosine kinase. PLoS Computational Biology 8:e1002661鈥揺1002661CrossRef
  61.de Beauch锚ne IC, Allain A, Panel N, Laine E, Trouv茅 A, et al. (2014) Hotspot mutations in kit receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity. PLoS Computational Biology 10:e1003749CrossRef
  62.Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, et al. (2012) Action of molecular switches in GPCRs-theoretical and experimental studies. Current Medicinal Chemistry 19:1090鈥?1109CrossRef
  63.Unal H, Karnik SS (2012) Domain coupling in GPCRs: the engine for induced conformational changes. Trends in Pharmacological Sciences 33:79鈥?8CrossRef
  64.Katritch V, Cherezov V, Stevens RC (2012) Diversity and modularity of G protein-coupled receptor structures. Trends in Pharmacological Sciences 33:17鈥?7CrossRef
  65.Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, et al. (2011) Crystal structure of the 尾2 adrenergic receptor-Gs protein complex. Nature 477:549鈥?55CrossRef
  66.Jaakola VP, Prilusky J, Sussman JL, Goldman A (2005) G protein-coupled receptors show unusual patterns of intrinsic unfolding. Protein Engineering, Design & Selection 18:103鈥?10CrossRef
  67.Gsponer J, Madan Babu M (2009) The rules of disorder or why disorder rules. Progress in Biophysics and Molecular Biology 99:94鈥?03CrossRef
  68.Babu MM, Kriwacki RW, Pappu RV (2012) Versatility from protein disorder. Science 337:1460鈥?461CrossRef
  69.Goetz A, Lanig H, Gmeiner P, Clark T (2011) Molecular dynamics simulations of the effect of the G-protein and diffusible ligands on the 尾2-adrenergic receptor. Journal of Molecular Biology 414:611鈥?23CrossRef
  70.Baker JG, Hill SJ (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends in Pharmacological Sciences 28:374鈥?81CrossRef
  71.Hermans E (2003) Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors. Pharmacology & Therapeutics 99:25鈥?4CrossRef
  72.Maudsley S, Martin B, Luttrell LM (2005) The origins of diversity and specificity in G protein-coupled receptor signaling. The Journal of Pharmacology and Experimental Therapeutics 314:485鈥?94CrossRef
  73.Pt谩膷ek R, Ku啪elov谩 H, Stefano GB (2011) Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Medical Science Monitor 17:RA215鈥?20
  74.L贸pez Le贸n S, Croes EA, Sayed-Tabatabaei FA, Claes S, Broeckhoven CV, et al. (2005) The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis. Biological Psychiatry 57:999鈥?003CrossRef
  75.Smalley S, Bailey J, Palmer C, Cantwell D, McGough J, et al. (1998) Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder. Molecular Psychiatry 3:427鈥?30CrossRef
  76.Grice D, Leckman J, Pauls D, Kurlan R, Kidd K, et al. (1996) Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test. American Journal of Human Genetics 59:644鈥?52
  77.Kenakin TP (2012) Biased signalling and allosteric machines: new vistas and challenges for drug discovery. British Journal of Pharmacology 165:1659鈥?669CrossRef
  78.Wieland K, Zuurmond HM, Krasel C, Ijzerman AP, Lohse MJ (1996) Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor. In: Proceedings of the National Academy of Sciences, vol 93, pp 9276鈥?281
  79.Kobilka BK (2007) G protein coupled receptor structure and activation. Biochimica et Biophysica Acta (BBA) - Biomembranes 1768:794鈥?07CrossRef
  80.O鈥橠owd BF, Hnatowich M, Regan J, Leader WM, Caron M, et al. (1988) Site-directed mutagenesis of the cytoplasmic domains of the human beta 2-adrenergic receptor. localization of regions involved in G protein-receptor coupling. The Journal of Biological Chemistry 263:15985鈥?5992
  81.Liggett S, Caron M, Lefkowitz R, Hnatowich M (1991) Coupling of a mutated form of the human beta 2-adrenergic receptor to Gi and Gs. requirement for multiple cytoplasmic domains in the coupling process. The Journal of Biological Chemistry 266:4816鈥?821
  82.Guan HC, Sunahara RK (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610鈥?14CrossRef
  
• 作者单位：Nidhi Jatana (1) (3)
  Lipi Thukral (2)
  N. Latha (1)
  
  1. Bioinformatics Infrastructure Facility, Sri Venkateswara College (University of Delhi), Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India
  3. CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
  2. CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

Human Dopamine Receptor D4 (DRD4) orchestrates several neurological functions and represents a target for many psychological disorders. Here, we examined two rare variants in DRD4; V194G and R237L, which elicit functional alterations leading to disruption of ligand binding and G protein coupling, respectively. Using atomistic molecular dynamics (MD) simulations, we provide in-depth analysis to reveal structural signatures of wild and mutant complexes with their bound agonist and antagonist ligands. We constructed intra-protein network graphs to discriminate the global conformational changes induced by mutations. The simulations also allowed us to elucidate the local side-chain dynamical variations in ligand-bound mutant receptors. The data suggest that the mutation in transmembrane V (V194G) drastically disrupts the organization of ligand binding site and causes disorder in the native helical arrangement. Interestingly, the R237L mutation leads to significant rewiring of side-chain contacts in the intracellular loop 3 (site of mutation) and also affects the distant transmembrane topology. Additionally, these mutations lead to compact ICL3 region compared to the wild type, indicating that the receptor would be inaccessible for G protein coupling. Our findings thus reveal unreported structural determinants of the mutated DRD4 receptor and provide a robust framework for design of effective novel drugs. Keywords GPCR Ligand binding Molecular dynamics simulations Mutations Intra-protein network