Prediction of the mechanism of action of omuralide (clasto-lactacystin β-lactone) on human cathepsin A based on a structural model of the yeast proteasome β5/PRE2-subunit/omuralide complex
Prediction of the mechanism of action of omuralide (clasto-lactacystin β-lactone) on human cathepsin A based on a structural model of the yeast proteasome β5/PRE2-subunit/omuralide complex
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DOI：
10.1016/j.bbapap.2006.05.008
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发表时间：
2006-08-01
影响因子：
3.2
通讯作者：
Itoh, Kohji
中科院分区：
文献类型：
--
作者：
Aikawa, Sei-ichi;Matsuzawa, Fumiko;Itoh, Kohji
组织蛋白酶A（CathA）是一种溶酶体丝氨酸羧肽酶，其与属于α/β-水解酶折叠家族的酵母和小麦丝氨酸羧肽酶（CPY和CPW）具有同源性和结构相似性。已证明人CathA（hCathA）和CPW可被蛋白酶体（苏氨酸蛋白酶）抑制剂lactacystin及其活性衍生物omuralide（裂体-lactacystin β-内酯）以及凝乳酶抑制剂抑制。一个hCathA/omuralide复合物模型的基础上构建的X-射线晶体结构的CPW/chymostatin复合物和酵母蛋白酶体β-亚基（β 5/PRE 2）/omuralide一个预测的构象omuralide在蛋白酶体β 5/PRE 2的活性位点裂缝应该是非常相似的，在S1催化亚位点的chymostatin在hCathA和CPW复合物。甘氨酸残基的相对位置，即存在于每种酶的氧阴离子孔中的hCathA中的Gly 57、CPW中的Gly 53和β 5/PRE 2中的Gly 47也高度保守。这些结果表明，omuralide可能会抑制hCathA和CPW的S1亚位点在其活性位点的裂缝，通过直接结合到活性丝氨酸残基。(c)2006 Elsevier B. V.保留所有权利。
Cathepsin A (CathA) is a lysosomal serine carboxypeptidase that exhibits homology and structural similarity to the yeast and wheat serine carboxypeptidases (CPY and CPW) belonging to the alpha/beta-hydrolase fold family. Human CathA (hCathA) and CPW have been demonstrated to be inhibited by a proteasome (threonine protease) inhibitor, lactacystin, and its active derivative, omuralide (clasto-lactacystin beta-lactone), as well as chymostatin. A hCathA/omuralide complex model constructed on the basis of the X-ray crystal structures of the CPW/chymostatin complex and the yeast proteasome beta-subunit (beta 5/PRE2)/omuralide one predicted that the conformation of omuralide in the active-site cleft of proteasome beta 5/PRE2 should be very similar to that of chymostatin at the S1 catalytic subsites in the hCathA- and CPW-complexes. The relative positions of the glycine residues, i.e., Gly57 in hCathA, Gly53 in CPW, and Gly47 in beta 5/PRE2, present in the oxyanion hole of each enzyme were also highly conserved. These results suggest that omuralide might inhibit hCathA and CPW at the S1 subsite in their active-site clefts through direct binding to the active serine residue. (c) 2006 Elsevier B.V. All rights reserved.