http://www.cnr.it/ontology/cnr/individuo/prodotto/ID17537
Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity (Articolo in rivista)
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- Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity (Articolo in rivista) (literal)
- Anno
- 2007-01-01T00:00:00+01:00 (literal)
- Alternative label
Tochowicz A., Maskos K., Huber R., Oltenfreiter R., Dive V., Yiotakis A., Zanda M., Bode W., Goettig P. (2007)
Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity
in Journal of Molecular Biology
(literal)
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- Tochowicz A., Maskos K., Huber R., Oltenfreiter R., Dive V., Yiotakis A., Zanda M., Bode W., Goettig P. (literal)
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- ISI Web of Science (WOS) (literal)
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- Anna Tochowicz1, Klaus Maskos1,2, Robert Huber3, Ruth Oltenfreiter4
Vincent Dive5, Athanasios Yiotakis6, Matteo Zanda7
Wolfram Bode1? and Peter Goettig1?
1Arbeitsgruppe
Proteinaseforschung,
Max-Planck-Institut für
Biochemie, Am Klopferspitz 18,
D-82152 Martinsried, Germany
2Proteros Biostructures GmbH,
Am Klopferspitz 19, D-82152
Martinsried, Germany
3Abteilung für
Strukturforschung,
Max-Planck-Institut für
Biochemie, Am Klopferspitz 18,
D-82152 Martinsried, Germany
4Faculty of Pharmaceutical
Sciences, Department of
Radiopharmacy, Ghent
University, Harelbekestraat 72,
9000 Ghent, Belgium
5CEA/iBiTecs, Service
d'Ingénierie Moléculaire des
Protéines (SIMOPRO),
Gif-sur-Yvette Cedex,
F-91191, France
6Laboratory of Organic
Chemistry, Department of
Chemistry, University of
Athens, Gr-15771 Athens,
Greece
7Istituto di Chimica del,
Riconoscimento Molecolare,
Via Mancinelli, 7,
20131 Milano, Italy (literal)
- Titolo
- Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity (literal)
- Abstract
- Human matrix metalloproteinase 9 (MMP-9), also called gelatinase B, is particularly involved in inflammatory processes, bone remodelling and wound healing, but is also implicated in pathological processes such as rheumatoid arthritis, atherosclerosis, tumour growth, and metastasis. We have prepared the inactive E402Q mutant of the truncated catalytic domain of human MMP-9 and co-crystallized it with active site-directed synthetic inhibitors of different binding types. Here, we present the X-ray structures of five MMP-9 complexes with gelatinase-specific, tight binding inhibitors: a phosphinic acid (AM-409), a pyrimidine-2,4,6-trione (RO-206-0222), two carboxylate (An-1 and MJ-24), and a trifluoromethyl hydroxamic acid inhibitor (MS-560). These compounds bind by making a compromise between optimal coordination of the catalytic zinc, favourable hydrogen bond formation in the active-site cleft, and accommodation of their large hydrophobic P1' groups in the slightly flexible S1 cavity, which exhibits distinct rotational conformations of the Pro421 carbonyl group in each complex. In all these structures, the side-chain of Arg424 located at the bottom of the S1' cavity is not defined in the electron density beyond C-gamma, indicating its mobility. However, we suggest that the mobile Arg424 side-chain partially blocks the S1' cavity, which might explain the weaker binding of most inhibitors with a long P1' side-chain for MMP-9 compared with the closely related MMP-2 (gelatinase A), which exhibits a short threonine side-chain at the equivalent position. These novel structural details should facilitate the design of more selective MMP-9 inhibitors. (literal)
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