1JK3

Crystal structure of human MMP-12 (Macrophage Elastase) at true atomic resolution

1JK3 の概要

• エントリーDOI: 10.2210/pdb1jk3/pdb
• 分子名称: MACROPHAGE METALLOELASTASE, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: matrix metalloproteinase, batimastat, bb94, hydroxamic acid, mmp12, elastase, complex (elastase-inhibitor), metallo elastase, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted, extracellular space, extracellular matrix (Probable): P39900
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18187.22

構造登録者

Lang, R.,Kocourek, A.,Braun, M.,Tschesche, H.,Huber, R.,Bode, W.,Maskos, K. (登録日: 2001-07-11, 公開日: 2001-09-28, 最終更新日: 2023-08-16)

主引用文献

Lang, R.,Kocourek, A.,Braun, M.,Tschesche, H.,Huber, R.,Bode, W.,Maskos, K.
Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure.
J.Mol.Biol., 312:731-742, 2001

PubMed Abstract: 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.

PubMed: 11575928
DOI: 10.1006/jmbi.2001.4954

実験手法

X-RAY DIFFRACTION (1.09 Å)