4h3x

Crystal structure of an MMP broad spectrum hydroxamate based inhibitor CC27 in complex with the MMP-9 catalytic domain

spinqualitylabelsall models 4h3x, resolution 1.76Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4h3x is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 10B, CA, GOL, PEG, PGO, ZN Related: 4h1q, 4h2e, 2ow1 Gene: mmp9, clg4b (HUMAN) Activity: Gelatinase B, with EC number 3.4.24.35 Resources: FirstGlance, OCA, RCSB, PDBsum Disease [MMP9_HUMAN] Defects in MMP9 may be a cause of susceptibility to intervertebral disc disease (IDD) [MIM:603932]; also known as lumbar disk herniation (LDH). IDD is one of the most common musculo-skeletal disorders and the predominant cause of low-back pain and unilateral leg pain. Defects in MMP9 are the cause of metaphyseal anadysplasia type 2 (MANDP2) [MIM:613073]. Metaphyseal anadysplasia consists of an abnormal bone development characterized by severe skeletal changes that, in contrast with the progressive course of most other skeletal dysplasias, resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. Function [MMP9_HUMAN] May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond. Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide. Publication Abstract from PubMed Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects. Crystallization of bi-functional ligand protein complexes.,Antoni C, Vera L, Devel L, Catalani MP, Czarny B, Cassar-Lajeunesse E, Nuti E, Rossello A, Dive V, Stura EA J Struct Biol. 2013 Apr 6. pii: S1047-8477(13)00086-5. doi:, 10.1016/j.jsb.2013.03.015. PMID:23567804 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Matrix metalloproteinase

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