Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.
Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling. Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis. Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein, has the shape of an elongated, contiguous wedge. With its long edge, consisting of five different chain regions, it occupies the entire length of the active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the catalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 side chain extends into the large specificity pocket of MMP-3. This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications.
Gomis-Rüth
F X
FX
Max-Planck-Institut für Biochemie, Abteilung für Strukturforschung, Martinsried, Germany.
Maskos
K
K
Betz
M
M
Bergner
A
A
Huber
R
R
Suzuki
K
K
Yoshida
N
N
Nagase
H
H
Brew
K
K
Bourenkov
G P
GP
Bartunik
H
H
Bode
W
W
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006023:Glycoproteins / Q000737:chemistry* / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D019278:Matrix Metalloproteinase 3