PMID- 9288970
OWN - NLM
STAT- MEDLINE
DCOM- 19970918
LR  - 20220318
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 389
IP  - 6646
DP  - 1997 Sep 4
TI  - Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by 
      TIMP-1.
PG  - 77-81
AB  - 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.
FAU - Gomis-Ruth, F X
AU  - Gomis-Ruth FX
AD  - Max-Planck-Institut fur Biochemie, Abteilung fur Strukturforschung, Martinsried, 
      Germany.
FAU - Maskos, K
AU  - Maskos K
FAU - Betz, M
AU  - Betz M
FAU - Bergner, A
AU  - Bergner A
FAU - Huber, R
AU  - Huber R
FAU - Suzuki, K
AU  - Suzuki K
FAU - Yoshida, N
AU  - Yoshida N
FAU - Nagase, H
AU  - Nagase H
FAU - Brew, K
AU  - Brew K
FAU - Bourenkov, G P
AU  - Bourenkov GP
FAU - Bartunik, H
AU  - Bartunik H
FAU - Bode, W
AU  - Bode W
LA  - eng
SI  - PDB/1UEA
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Glycoproteins)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Drug Design
MH  - Glycoproteins/*chemistry/pharmacology
MH  - Glycosylation
MH  - Humans
MH  - Matrix Metalloproteinase 3/*chemistry
MH  - Matrix Metalloproteinase Inhibitors
MH  - Models, Molecular
MH  - Protease Inhibitors/chemical synthesis/*chemistry/pharmacology
MH  - Protein Conformation
MH  - Tissue Inhibitor of Metalloproteinases
EDAT- 1997/09/04 00:00
MHDA- 2001/03/23 10:01
CRDT- 1997/09/04 00:00
PHST- 1997/09/04 00:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1997/09/04 00:00 [entrez]
AID - 10.1038/37995 [doi]
PST - ppublish
SO  - Nature. 1997 Sep 4;389(6646):77-81. doi: 10.1038/37995.