Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain.

Enrico A Stura; Robert Visse; Philippe CuniasseVincent DiveHideaki Nagase

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Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain.

机译：全长人胶原酶 3 （MMP-13）的晶体结构与活性位点中的肽定义了催化结构域中的外位点。

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Matrix metalloproteinase (MMP)-13 is one of the mammalian collagenases that play key roles in tissue remodelling and repair and in progression of diseases such as cancer, arthritis, atherosclerosis, and aneurysm. For collagenase to cleave triple helical collagens, the triple helical structure has to be locally unwound before hydrolysis, but this process is not well understood. We report crystal structures of catalytically inactive full-length human MMP-13(E223A) in complex with peptides of 14-26 aa derived from the cleaved prodomain during activation. Peptides are bound to the active site of the enzyme by forming an extended β-strand with Glu(40) or Tyr(46) inserted into the S1' specificity pocket. The structure of the N-terminal part of the peptides is variable and interacts with different parts of the catalytic domain. Those areas are designated substrate-dependent exosites, in that they accommodate different peptide structures, whereas the precise positioning of the substrate backbone is maintained in the active site. These modes of peptide-MMP-13 interactions have led us to propose how triple helical collagen strands fit into the active site cleft of the collagenase.-Stura, E. A., Visse, R., Cuniasse, P., Dive, V., Nagase, H. Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain.

机译：基质金属蛋白酶（MMP）-13 是哺乳动物胶原酶之一，在组织重塑和修复以及癌症、关节炎、动脉粥样硬化和动脉瘤等疾病的进展中起关键作用。对于胶原酶切割三螺旋胶原，三螺旋结构必须在水解前局部展开，但这一过程尚不清楚。我们报道了催化失活的全长人 MMP-13 （E223A）的晶体结构，复合物在激活过程中来自裂解的前结构域的 14-26 aa 肽。肽通过形成延伸的 β 链与酶的活性位点结合，将 Glu（40）或 Tyr（46）插入 S1' 特异性口袋中。肽的N端部分的结构是可变的，并且与催化结构域的不同部分相互作用。这些区域被指定为底物依赖性外位点，因为它们容纳不同的肽结构，而底物骨架的精确定位保持在活性位点中。这些肽-MMP-13相互作用模式使我们提出了三螺旋胶原链如何适应胶原酶的活性位点裂隙.-Stura， E. A.， Visse， R.， Cuniasse， P.， Dive， V.， Nagase， H. 全长人胶原酶3（MMP-13）的晶体结构与活性位点中的肽定义了催化结构域中的外位点。

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来源
《The FASEB Journal》 |2013年第11期|4395-4405|共11页
作者
Enrico A Stura; Robert Visse; Philippe CuniasseVincent DiveHideaki Nagase;
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2H.N., Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and;

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正文语种英语
中图分类生物化学;
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Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain.

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