Crystal Structure of the Disintegrin Heterodimer from Saw-Scaled Viper (Echis carinatus) at 1.9 Å Resolution

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• 作者：Sameeta Bilgrami ; Savita Yadav ; Punit Kaur ; Sujata Sharma ; Markus Perbandt ; Christian Betzel ; and Tej P. Singh
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：August 23, 2005
• 年：2005
• 卷：44
• 期：33
• 页码：11058 - 11066
• 全文大小：513K
• 年卷期：v.44,no.33(August 23, 2005)
• ISSN：1520-4995

文摘

Disintegrins constitute a family of potent polypeptide inhibitors of integrins. Integrins aretransmembrane heterodimeric molecules involved in cell-cell and cell-extracellular matrix interactions.They are involved in many diseases such as cancer and thrombosis. Thus, disintegrins have a great potentialas anticancer and antithrombotic agents. A novel heterodimeric disintegrin was isolated from the venomof saw-scaled viper (Echis carinatus) and was crystallized. The crystals diffracted to 1.9 Å resolution andbelonged to space group P4₃2₁2. The data indicated the presence of a pseudosymmetry. The structurewas solved by applying origin shifts to the disintegrin homodimer schistatin solved in space group I4₁22with similar cell dimensions. The structure refined to the final R_cryst/R_free factors of 0.213/0.253. Thenotable differences are observed between the loops, (Gln39-Asp48) containing the important Arg42-Gly43-Asp44, of the present heterodimer and schistatin. These differences are presumably due to thepresence of two glycines at positions 43 and 46 that allow the molecule to adopt variable conformations.A comparative analysis of the surface-charge distributions of various disintegrins showed that the chargedistribution on monomeric disintegrins occurred uniformly over the whole surface of the molecule, whilein the dimeric disintegrins, the charge is distributed only on one face. Such a feature may be importantin the binding of two integrins to a single dimeric disintegrin. The phylogenetic analysis developed onthe basis of amino acid sequence and three-dimensional structures indicates that the protein diversificationand evolution presumably took place from the medium disintegrins and both the dimeric and shortdisintegrins evolved from them.