Insight into the stereochemistry in the inhibition of carboxypeptidase A with N-(hydroxyaminocarbonyl)phenylalanine:: Binding modes of an enantiomeric pair of the inhibitor to carboxypeptidase A
Insight into the stereochemistry in the inhibition of carboxypeptidase A with N-(hydroxyaminocarbonyl)phenylalanine:: Binding modes of an enantiomeric pair of the inhibitor to carboxypeptidase A
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DOI：
10.1016/s0968-0896(01)00429-1
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发表时间：
2002-06-01
影响因子：
3.5
通讯作者：
Choi, KY
中科院分区：
文献类型：
--
作者：
Cho, JH;Kim, DH;Choi, KY
N-（羟基氨基羰基）苯丙氨酸（1）的D-和L-异构体均显示对羧肽酶A（CPA）具有强结合亲和力，其中D-1比其对映体强3倍（Chung，S. J.道：Kim，D. H. Bioorg. 2001，9，185.）。为了理解CPA抑制中显示的反向立体化学偏好，我们已经解决了CPA与1至1.75埃分辨率的每个对映体络合的晶体结构。抑制剂L-1的立体化学属于底物的立体化学系列，其与CPA的结合类似于底物，其羰基氧与活性位点锌离子配位。其羟基与Glu-270的羧酸根形成氢键。另一方面，在D-I与CPA的结合中，其末端羟基参与与活性位点锌离子和Glu-270的羧酸根的相互作用。在两个CPA（.）1络合物中，I中的苯环在S-1'亚位点处被装配在底物识别口袋中，并且抑制剂的羧酸盐与Arg-145的胍部分形成分叉氢键，与Arg-127的胍形成氢键。在CPA（.）D-1，抑制剂的羧酸酯与下位Tyr-248的酚羟基形成氢键。虽然L-1结合诱导活性位点处的骨架氨基酸残基的协同运动，但当D-1结合CPA时，仅注意到Tyr-248的向下运动。(C)2002爱思唯尔科技有限公司。保留所有权利。
Both D- and L-isomers of N-(hydroxyaminocarbonyl)phenylalanine (1) were shown to have strong binding affinity towards carboxypeptidase A (CPA) with D-1 being more potent than its enantiomer by 3-fold (Chung, S. J.; Kim, D. H. Bioorg. Med. Chem. 2001, 9, 185.). In order to understand the reversed stereochemical preference shown in the CPA inhibition, we have solved the crystal structures of CPA complexed with each enantiometer of 1 up to 1.75 Angstrom resolution. Inhibitor L-1 whose stereochemistry belongs to the stereochemical series of substrate binds CPA like substrate does with its carbonyl oxygen coordinating to the active site zinc ion. Its hydroxyl is engaged in hydrogen bonding with the carboxylate of Glu-270. On the other hand, in binding Of D- I to CPA, its terminal hydroxyl group is involved in interactions with the active site zinc ion and the carboxylate of Glu-270. In both CPA(.)1 complexes, the phenyl ring in I is fitted in the substrate recognition pocket at the S-1' subsite, and the carboxylate of the inhibitors forms bifurcated hydrogen bonds with the guanidinium moiety of Arg-145 and a hydrogen bond with the guanidinium of Arg-127. In the complex of CPA(.)D-1, the carboxylate of the inhibitor is engaged in hydrogen bonding with the phenolic hydroxyl of the down-positioned Tyr-248. While the L-1 binding induces a concerted movement of the backbone amino acid residues at the active site, only the downward movement of Tyr-248 was noted when D-1 binds to CPA. (C) 2002 Elsevier Science Ltd. All rights reserved.