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与batimastat复合的人ADAM-8催化结构域的结构

Structure of human ADAM-8 catalytic domain complexed with batimastat.

作者信息

Hall Troii, Shieh Huey Sheng, Day Jacqueline E, Caspers Nicole, Chrencik Jill E, Williams Jennifer M, Pegg Lyle E, Pauley Adele M, Moon Andrea F, Krahn Joseph M, Fischer David H, Kiefer James R, Tomasselli Alfredo G, Zack Marc D

机构信息

Pfizer Inc, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA.

出版信息

Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Jun 1;68(Pt 6):616-21. doi: 10.1107/S1744309112015618. Epub 2012 May 22.

DOI:10.1107/S1744309112015618
PMID:22684055
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3370895/
Abstract

The role of ADAM-8 in cancer and inflammatory diseases such as allergy, arthritis and asthma makes it an attractive target for drug development. Therefore, the catalytic domain of human ADAM-8 was expressed, purified and crystallized in complex with a hydroxamic acid inhibitor, batimastat. The crystal structure of the enzyme-inhibitor complex was refined to 2.1 Å resolution. ADAM-8 has an overall fold similar to those of other ADAM members, including a central five-stranded β-sheet and a catalytic Zn(2+) ion. However, unique differences within the S1' binding loop of ADAM-8 are observed which might be exploited to confer specificity and selectivity to ADAM-8 competitive inhibitors for the treatment of diseases involving this enzyme.

摘要

ADAM-8在癌症以及诸如过敏、关节炎和哮喘等炎症性疾病中所起的作用，使其成为药物研发的一个有吸引力的靶点。因此，人ADAM-8的催化结构域得以表达、纯化，并与一种异羟肟酸抑制剂batimastat形成复合物后进行结晶。该酶-抑制剂复合物的晶体结构被精修至2.1 Å的分辨率。ADAM-8的整体折叠结构与其他ADAM家族成员相似，包括一个中心的五链β-折叠片层和一个催化性Zn(2+)离子。然而，在ADAM-8的S1'结合环内观察到了独特的差异，这些差异可能被用于赋予ADAM-8竞争性抑制剂特异性和选择性，以治疗涉及该酶的疾病。

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