1ums: Difference between revisions
No edit summary |
No edit summary |
||
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
Stromelysin, a representative matrix metalloproteinase and target of drug | Stromelysin, a representative matrix metalloproteinase and target of drug development efforts, plays a prominent role in the pathological proteolysis associated with arthritis and secondarily in that of cancer metastasis and invasion. To provide a structural template to aid the development of therapeutic inhibitors, we have determined a medium-resolution structure of a 20-kDa complex of human stromelysin's catalytic domain with a hydrophobic peptidic inhibitor using multinuclear, multidimensional NMR spectroscopy. This domain of this zinc hydrolase contains a mixed beta-sheet comprising one antiparallel strand and four parallel strands, three helices, and a methionine-containing turn near the catalytic center. The ensemble of 20 structures was calculated using, on average, 8 interresidue NOE restraints per residue for the 166-residue protein fragment complexed with a 4-residue substrate analogue. The mean RMS deviation (RMSD) to the average structure for backbone heavy atoms is 0.91 A and for all heavy atoms is 1.42 A. The structure has good stereochemical properties, including its backbone torsion angles. The beta-sheet and alpha-helices of the catalytic domains of human stromelysin (NMR model) and human fibroblast collagenase (X-ray crystallographic model of Lovejoy B et al., 1994b, Biochemistry 33:8207-8217) superimpose well, having a pairwise RMSD for backbone heavy atoms of 2.28 A when three loop segments are disregarded. The hydroxamate-substituted inhibitor binds across the hydrophobic active site of stromelysin in an extended conformation. The first hydrophobic side chain is deeply buried in the principal S'1 subsite, the second hydrophobic side chain is located on the opposite side of the inhibitor backbone in the hydrophobic S'2 surface subsite, and a third hydrophobic side chain (P'3) lies at the surface. | ||
==Disease== | ==Disease== | ||
| Line 17: | Line 17: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Stromelysin 1]] | [[Category: Stromelysin 1]] | ||
[[Category: Doren, S | [[Category: Doren, S R.Van.]] | ||
[[Category: Hu, W.]] | [[Category: Hu, W.]] | ||
[[Category: Kurochkin, A | [[Category: Kurochkin, A V.]] | ||
[[Category: Zuiderweg, E | [[Category: Zuiderweg, E R.P.]] | ||
[[Category: CA]] | [[Category: CA]] | ||
[[Category: HAE]] | [[Category: HAE]] | ||
| Line 29: | Line 29: | ||
[[Category: zinc hydrolase]] | [[Category: zinc hydrolase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:26:13 2008'' | ||
Revision as of 16:26, 21 February 2008
|
STROMELYSIN-1 CATALYTIC DOMAIN WITH HYDROPHOBIC INHIBITOR BOUND, PH 7.0, 32OC, 20 MM CACL2, 15% ACETONITRILE; NMR ENSEMBLE OF 20 STRUCTURES
OverviewOverview
Stromelysin, a representative matrix metalloproteinase and target of drug development efforts, plays a prominent role in the pathological proteolysis associated with arthritis and secondarily in that of cancer metastasis and invasion. To provide a structural template to aid the development of therapeutic inhibitors, we have determined a medium-resolution structure of a 20-kDa complex of human stromelysin's catalytic domain with a hydrophobic peptidic inhibitor using multinuclear, multidimensional NMR spectroscopy. This domain of this zinc hydrolase contains a mixed beta-sheet comprising one antiparallel strand and four parallel strands, three helices, and a methionine-containing turn near the catalytic center. The ensemble of 20 structures was calculated using, on average, 8 interresidue NOE restraints per residue for the 166-residue protein fragment complexed with a 4-residue substrate analogue. The mean RMS deviation (RMSD) to the average structure for backbone heavy atoms is 0.91 A and for all heavy atoms is 1.42 A. The structure has good stereochemical properties, including its backbone torsion angles. The beta-sheet and alpha-helices of the catalytic domains of human stromelysin (NMR model) and human fibroblast collagenase (X-ray crystallographic model of Lovejoy B et al., 1994b, Biochemistry 33:8207-8217) superimpose well, having a pairwise RMSD for backbone heavy atoms of 2.28 A when three loop segments are disregarded. The hydroxamate-substituted inhibitor binds across the hydrophobic active site of stromelysin in an extended conformation. The first hydrophobic side chain is deeply buried in the principal S'1 subsite, the second hydrophobic side chain is located on the opposite side of the inhibitor backbone in the hydrophobic S'2 surface subsite, and a third hydrophobic side chain (P'3) lies at the surface.
DiseaseDisease
Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[185250]
About this StructureAbout this Structure
1UMS is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Stromelysin 1, with EC number 3.4.24.17 Full crystallographic information is available from OCA.
ReferenceReference
Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor., Van Doren SR, Kurochkin AV, Hu W, Ye QZ, Johnson LL, Hupe DJ, Zuiderweg ER, Protein Sci. 1995 Dec;4(12):2487-98. PMID:8580839
Page seeded by OCA on Thu Feb 21 15:26:13 2008