Human Fibroblast Collagenase (MMP-1, matrix metalloproteinase)
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Average MMP-1 inhibitor free structure The His side-chains binding to the structural and active-site Zn are shown as licorice bonds. The active site and structural Zn and Ca are shown as Van der Waal spheres. PDBID: 2AYK Structure published in: Biochemistry (1998) 37 (6), 1495-1504. |
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Average MMP-1 inhibitor free structure using RDCs The His side-chains binding to the structural and active-site Zn are shown as licorice bonds. The active site and structural Zn and Ca are shown as Van der Waal spheres. Structure published in: Biochemistry (2000) 39(44), 13365-13375 |
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MMP-1:CGS-27023A structure The His side-chains binding to the structural and active-site Zn are shown as licorice bonds. The active site and structural Zn and Ca are shown as Van der Waal spheres. The inhibitor is also shown as licorice bonds and colored red. PDBID:3AYK Structure published in: Biochemistry (1999) 38(22) 7085-7096. |
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MMP-1:CPD-230 structures Difference Between First and Second Conformation is fast exchange of acetylene group. Difference Between (First/Second) and (Third/Fourth) is slow exchange of two binding modes The His side-chains binding to the structural and active-site Zn are shown as licorice bonds. The active site and structural Zn and Ca are shown as Van der Waal spheres. The inhibitor is also shown as licorice bonds and colored red. Created from: PDBID:3AYK Published in: Biochemistry (1999) 38(22) 7085-7096. Structure published in: JACS (2002), 124(43) 12658-12659 |
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Fibroblast collagenase (MMP-1) is a member of the matrix metalloproteinase (MMP) family which include the collagenases, stromelysins and gelatinases. These enzymes require zinc and calcium for activity and are modular with both propeptide and catalytic domains being common to the entire family.The design of inhibitors of various MMPs for use as therapeutic agents in the treatment of arthritis and cancer has been an exceptionally active area of research. The MMPs are involved in the degradation of the extracellular matrix that is associated with normal tissue remodeling and, as result, MMP expression and activity is highly controlled by either specific inhibitors (tissue inhibitor of metalloendoproteases - TIMP), by cleavage of the inactive proenzyme or by transcription induction or suppression. A number of biochemical stimuli including cytokines, hormones, oncogene products and tumor promoters effect the synthesis and activation of MMPs. The apparent loss in this regulation can result in the pathological destruction of connective tissue and an ensuing disease state. The MMP family consists of more than 25 enzymes, and it has been postulated that the toxicity demonstrated by many MMP inhibitors in clinical trials may result from non-specific inhibition. Thus, the current approach relies on structure-based design of inhibitors of specific MMPs, where selectivity against MMP-1 may be a desirable trait. The extensive structural data available for the MMPs has enabled the identification of an obvious approach for designing specificity by taking advantage of the sequence difference and distinct size and shape of the S1’ pocket. A number of examples have been previously reported using this approach. Nevertheless, the observed mobility of the MMP active site may complicate the design of potentially selective inhibitors.
We determined the first structure of a free MMP (MMP-1), where the dynamic analysis was first to indicate that the active sight of MMPs are dynamic and flexible where a slow conformational exchange for residues comprising the active site (helix B, zinc ligated histidines and the nearby loop region) and a high mobility for residues P138-G144 in the vicinity of the active site for inhibitor-free MMP-1 was observed. Furthermore, analysis of inhibitors predicted to be selected against MMP-1 were surprisingly identified to bind tightly (picomolar) to the enzyme due to the observed dynamics by NMR of both the MMPs and the ligand. Numerous inhibitors complexed to both MMP-1 and MMP-13 have been determined utilizing a hybrid approach to quickly determine the corresponding co-structures. This was first described for the MMP-1:CGS-27023A structure.