1jk3
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Crystal structure of human MMP-12 (Macrophage Elastase) at true atomic resolution
OverviewOverview
The macrophage elastase enzyme (MMP-12) expressed mainly in alveolar, macrophages has been identified in the mouse lung as the main destructive, agent associated with cigarette smoking, which gives rise to emphysema, both directly via elastin degradation and indirectly by disturbing the, proteinase/antiproteinase balance via inactivation of the, alpha1-proteinase inhibitor (alpha1-PI), the antagonist of the leukocyte, elastase. The catalytic domain of human recombinant MMP-12 has been, crystallized in complex with the broad-specificity inhibitor batimastat, (BB-94). The crystal structure analysis of this complex, determined using, X-ray data to 1.1 A and refined to an R-value of 0.165, reveals an overall, fold similar to that of other MMPs. However, the S-shaped double loop, connecting strands III and IV is fixed closer to the beta-sheet and, projects its His172 side-chain further into the rather hydrophobic, active-site cleft, defining the S3 and the S1-pockets and separating them, from each other to a larger extent than is observed in other MMPs. The, S2-site is planar, while the characteristic S1'-subsite is a continuous, tube rather than a pocket, in which the MMP-12-specific Thr215 replaces a, Val residue otherwise highly conserved in almost all other MMPs. This, alteration might allow MMP-12 to accept P1' Arg residues, making it unique, among MMPs. The active-site cleft of MMP-12 is well equipped to bind and, efficiently cleave the AlaMetPhe-LeuGluAla sequence in the reactive-site, loop of alpha1-PI, as occurs experimentally. Similarities in contouring, and particularly a common surface hydrophobicity both inside and distant, from the active-site cleft explain why MMP-12 shares many substrates with, matrilysin (MMP-7). The MMP-12 structure is an excellent template for the, structure-based design of specific inhibitors for emphysema therapy and, for the construction of mutants to clarify the role of this MMP.
DiseaseDisease
Known diseases associated with this structure: Cardiomyopathy, dilated, 1G OMIM:[188840], Cardiomyopathy, familial hypertrophic OMIM:[188840], Muscular dystrophy, limb-girdle, type 2J OMIM:[188840], Myopathy, proximal, with early respiratory muscle involvement OMIM:[188840], Tibial muscular dystrophy, tardive OMIM:[188840]
About this StructureAbout this Structure
1JK3 is a Single protein structure of sequence from Homo sapiens with ZN, CA and BAT as ligands. Active as Macrophage elastase, with EC number 3.4.24.65 Full crystallographic information is available from OCA.
ReferenceReference
Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure., Lang R, Kocourek A, Braun M, Tschesche H, Huber R, Bode W, Maskos K, J Mol Biol. 2001 Sep 28;312(4):731-42. PMID:11575928
Page seeded by OCA on Mon Nov 12 17:41:22 2007