Robinson David A, Stewart Kirsty A, Price Nicholas C, Chalk Peter A, Coggins John R, Lapthorn Adrian J
Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
J Med Chem. 2006 Feb 23;49(4):1282-90. doi: 10.1021/jm0505361.
The crystal structures of the type II dehydroquinase (DHQase) from Helicobacter pylori in complex with three competitive inhibitors have been determined. The inhibitors are the substrate analogue 2,3-anhydroquinate (FA1), citrate, and an oxoxanthene sulfonamide derivative (AH9095). Despite the very different chemical nature of the inhibitors, in each case the primary point of interaction with the enzyme is via the residues that bind the C1 functionalities of the substrate, 3-dehydroquinate, i.e., N76, H102, I103, and H104. The DHQase/AH9095 complex crystal structure shows that sulfonamides can form a scaffold for nonsubstrate-like inhibitors and identifies a large conserved hydrophobic patch at the entrance to the active site as a locus that can be exploited in the development of new ligands.
已确定幽门螺杆菌II型脱氢奎尼酸酶（DHQase）与三种竞争性抑制剂复合物的晶体结构。这些抑制剂分别是底物类似物2,3-脱水奎尼酸（FA1）、柠檬酸盐和一种氧杂蒽磺酰胺衍生物（AH9095）。尽管这些抑制剂的化学性质差异很大，但在每种情况下，与酶的主要相互作用点都是通过与底物3-脱氢奎尼酸的C1官能团结合的残基，即N76、H102、I103和H104。DHQase/AH9095复合物晶体结构表明，磺酰胺可以形成非底物样抑制剂的支架，并确定活性位点入口处一个大的保守疏水区域是可用于开发新配体的位点。
