X-RAY CRYSTALLOGRAPHIC ANALYSIS OF INHIBITION OF ENDOTHIAPEPSIN BY CYCLOHEXYL RENIN INHIBITORS
X-RAY CRYSTALLOGRAPHIC ANALYSIS OF INHIBITION OF ENDOTHIAPEPSIN BY CYCLOHEXYL RENIN INHIBITORS
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DOI：
10.1021/bi00150a005
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发表时间：
1992-09-08
期刊：
影响因子：
2.9
通讯作者：
DUNN, BM
中科院分区：
文献类型：
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作者：
COOPER, J;QUAIL, W;DUNN, BM
内皮硫肽酶，一种真菌天冬氨酸蛋白酶（EC 3.4.23.6），与两种寡肽肾素抑制剂，PD 125967和PD 125754共结晶的晶体结构，已确定在2.0埃的分辨率和细化的R-因子分别为0.143和0.153。这些抑制剂分别为羟乙烯和他汀类，在P1处具有环己基丙氨酸侧链，并在P3位置具有有趣的功能，到目前为止，尚未进行晶体学分析。PD 125967在P3处具有双（1-萘甲基）乙酰基残基，PD 125754具有P3-P2肽键的羟基磷灰石类似物，用于蛋白水解稳定性。结构表明，S3口袋容纳一个萘基环与构象变化的Asp 77和Asp 114侧链，其他萘基基团驻留在S4区域。PD 125754的P3-P2羟脯氨酸类似物与Thr 219的NH形成氢键，从而与迄今为止研究的所有抑制剂的等效肽基团与酶产生相同的相互作用。在该抑制剂的P2和P1'位置处不存在侧链允许水分子占据复合物中的相应口袋。PD 125967和PD 125754对内皮硫蛋白酶的相对效力与抑制剂结合时发生的溶剂可及面积的变化一致。
The crystal structures of endothiapepsin, a fungal aspartic proteinase (EC 3.4.23.6), cocrystallized with two oligopeptide renin inhibitors, PD125967 and PD125754, have been determined at 2.0-angstrom resolution and refined to R-factors of 0.143 and 0.153, respectively. These inhibitors, which are of the hydroxyethylene and statine types, respectively, possess a cyclohexylalanine side chain at P1 and have interesting functionalities at the P3 position which, until now, have not been subjected to crystallographic analysis. PD125967 has a bis(1-naphthylmethyl)acetyl residue at P3, and PD125754 possesses a hydroxyethylene analogue of the P3-P2 peptide bond for proteolytic stability. The structures reveal that the S3 pocket accommodates one naphthyl ring with conformational changes of the Asp 77 and Asp 114 side chains, the other naphthyl group residing in the S4 region. The P3-P2 hydroxyethylene analogue of PD 125754 forms a hydrogen bond with the NH of Thr 219, thereby making the same interaction with the enzyme as the equivalent peptide groups of all inhibitors studied so far. The absence of side chains at the P2 and P1' positions of this inhibitor allows water molecules to occupy the respective pockets in the complex. The relative potencies of PD125967 and PD125754 for endothiapepsin are consistent with the changes in solvent-accessible area which take place on inhibitor binding.