期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1803, 期 1, 页码 29-38出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2009.04.010
关键词
Allostery; Allosteric regulation; Matrix metalloproteinase (MMP); Protein flexibility/hemopexin domain; Fibronectin domain; Exosite; Protein conformation
资金
- Israel Science Foundation
- Kimmelman Center at the Weizmann Institute
- Ambach family fund
- Weizmann-UK fund
The zinc-dependent matrix metalloproteinases (MMPs) belong to a large family of structurally homologous enzymes. These enzymes are involved in a wide variety of biological processes ranging from physiological cell proliferation and differentiation to pathological states associated with tumor metastasis, inflammation, tissue degeneration, and cell death. Controlling the enzymatic activity of specific individual MMPs by antagonist molecules is highly desirable, first, for studying their individual roles, and second as potential therapeutic agents. However, blocking the enzymatic activity with synthetic small inhibitors appears to be an extremely difficult task. Thus, this is an unmet need presumably due to the high structural homology between MMP catalytic domains. Recent reports have recognized a potential role for exosite or allosteric protein regions, distinct from the extended catalytic pocket, in mediating MMP activation and substrate hydrolysis. This raises the possibility that MMP enzymatic and non-enzymatic activities may be modified via antagonist molecules targeted to such allosteric sites or to alternative enzyme domains. in this review, we discuss the structural and functional bases for potential allosteric control of MMPs and highlight potential alternative enzyme domains as targets for designing highly selective MMP inhibitors. (C) 2009 Published by Elsevier B.V.
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