MATRILYSIN-INHIBITOR COMPLEXES - COMMON THEMES AMONG METALLOPROTEASES
MATRILYSIN-INHIBITOR COMPLEXES - COMMON THEMES AMONG METALLOPROTEASES
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DOI：
10.1021/bi00020a004
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发表时间：
1995-05-23
期刊：
影响因子：
2.9
通讯作者：
CASTELHANO, AL
中科院分区：
文献类型：
--
作者：
BROWNER, MF;SMITH, WW;CASTELHANO, AL
基质金属蛋白酶是在细胞外基质的生理和病理降解中起关键作用的酶家族。这些酶可能是治疗各种疾病的重要治疗靶标，其中组织降解是病理学的一部分，例如癌症和关节炎。基质溶素是这个酶家族中最小的成员，所有这些酶都需要锌来进行催化活性。首次报道了人基质溶解素的X射线晶体结构。金属蛋白酶的抑制剂通常以与蛋白质的活性位点锌相互作用的化学基团为特征。基质溶解素与异羟肟酸盐（最大分辨率1.9埃），羧酸盐（最大分辨率2.4埃）和硫代二亚胺（最大分辨率2.3埃）抑制剂复合的结构在这里介绍，并提供有关每个官能团如何与催化锌相互作用的详细信息。在该系列缓蚀剂中，只有锌配位基团是可变的。检查这些通道matrilysin复合物强调锌配位基团在确定抑制剂的相对效力中发挥的主导作用。这些基质溶解素-抑制剂复合物的结构也为比较MMPs和其他金属蛋白的催化机制提供了基础，
Matrix metalloproteases are a family of enzymes that play critical roles in the physiological and pathological degradation of the extracellular matrix. These enzymes may be important therapeutic targets for the treatment of various diseases where tissue degradation is part of the pathology, such as cancer and arthritis. Matrilysin is the smallest member of this family of enzymes, all of which require zinc for catalytic activity. The first X-ray crystal structures of human matrilysin are presented. inhibitors of metalloproteases are often characterized by the chemical group that interacts with the active site zinc of the protein. The structures of matrilysin complexed with hydroxamate (maximum resolution 1.9 Angstrom), carboxylate (maximum resolution 2.4 Angstrom), and sulfodiimine (maximum resolution 2.3 Angstrom) inhibitors are presented here and provide detailed information about how each functional group interacts with the catalytic zinc. Only the zinc-coordination group is variable in this series of inhibitors. Examination of these inhibitor-matrilysin complexes emphasizes the dominant role the zinc-coordinating group plays in determining the relative potencies of the inhibitors. The structures of these matrilysin-inhibitor complexes also provide a basis for comparing the catalytic mechanism of MMPs and other metalloproteins,