Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition?
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.
Sela-Passwell
Netta
N
Department of Structural Biology, The Weizmann Institute of Science, Israel.
Rosenblum
Gabriel
G
Shoham
Tsipi
T
Sagi
Irit
I
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology
D019138:Antibodies, Blocking; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases