3ma2

Complex membrane type-1 matrix metalloproteinase (MT1-MMP) with tissue inhibitor of metalloproteinase-1 (TIMP-1)

spinqualitylabelsall models 3ma2, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3ma2 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: CA, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MMP14_HUMAN Seems to specifically activate progelatinase A. May thus trigger invasion by tumor cells by activating progelatinase A on the tumor cell surface. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Protein flexibility is thought to play key roles during numerous biological processes including antibody affinity maturation, signal transduction and enzyme catalysis. Yet only limited information is available regarding the molecular details linking protein dynamics with function. A single point mutation at the distal site of the endogenous tissue inhibitor of metalloproteinase-1 (TIMP-1) enables this clinical target protein to tightly bind and inhibit membrane type-1 matrix metalloproteinase (MT1-MMP) by increasing only the association constant. The high resolution x-ray structure of this complex determined at 2A could not explain the mechanism of enhanced binding, and pointed to a role for protein conformational dynamics. Molecular dynamics (MD) simulations reveal that the high-affinity TIMP-1 mutants exhibit significantly reduced binding interface flexibility and more stable hydrogen bond networks. This was accompanied by redistribution of the ensemble of substrates to favorable binding conformations that fit the enzyme catalytic site. Apparently, the decrease in backbone flexibility lead to lower entropy cost upon complex formation. This work quantifies the effect of a single point mutation on protein conformational dynamics and function of TIMP-1. Here we argue that controlling intrinsic protein dynamics of MMPs endogenous inhibitors may be utilized for rationalizing the design of selective novel protein inhibitors for this class of enzymes. Intrinsic protein flexibility of endogenous protease inhibitor TIMP-1 controls its binding interface and effects its function.,Grossman M, Tworowski D, Dym O, Lee MH, Levy Y, Murphy G, Sagi I Biochemistry. 2010 Jun 14. PMID:20545310 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Matrix metalloproteinase Matrix metalloproteinase 3D structures

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