Structural basis for potent slow binding inhibition of human matrix metalloproteinase-2 (MMP-2).
The zinc-dependent gelatinases belong to the family of matrix metalloproteinases (MMPs), enzymes that have been shown to play a key role in angiogenesis and tumor metastasis. These enzymes are capable of hydrolyzing extracellular matrix (ECM) components under physiological conditions. Specific and selective inhibitors aimed at blocking their activity are highly sought for use as potential therapeutic agents. We report herein on a novel mode of inhibition of gelatinase A (MMP-2) by the recently characterized inhibitors 4-(4-phenoxphenylsulfonyl)butane-1,2-dithiol (inhibitor 1) and 5-(4-phenoxphenylsulfonyl) pentane-1,2-dithiol (inhibitor 2). These synthetic inhibitors are selective for MMP-2 and MMP-9. We show that the dithiolate moiety of these inhibitors chelates the catalytic zinc ion of MMP-2 via two sulfur atoms. This mode of binding results in alternation of the coordination number of the metal ion and the induction of conformational changes at the microenvironment of the catalytic zinc ion; a set of events that is likely to be at the root of the potent slow binding inhibition behavior exhibited by these inhibitors. This study demonstrates a distinct approach for the understanding of the structural mechanism governing the molecular interactions between potent inhibitors and catalytic sites of MMPs, which may aid in the design of effective inhibitors.
Rosenblum
Gabriel
G
Department of Structural Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
Meroueh
Samy O
SO
Kleifeld
Oded
O
Brown
Stephen
S
Singson
Steven P
SP
Fridman
Rafael
R
Mobashery
Shahriar
S
Sagi
Irit
I
D020134:Catalytic Domain; D002942:Circular Dichroism; D015195:Drug Design; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013057:Spectrum Analysis; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology; D014965:X-Rays; D015032:Zinc / Q000737:chemistry
C476617:4-(4-phenoxyphenylsulfonyl)butane-1,2-dithiol; C476618:5-(4-phenoxyphenylsulfonyl)pentane-1,2-dithiol; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; D013450:Sulfones; D020778:Matrix Metalloproteinase 2; D015032:Zinc