The NMR structure of the inhibited catalytic domain of human stromelysin–1

Gooley, Paul R.; O’Connell, John F.; Marcy, Alice I.; Cuca, Gregory C.; Salowe, Scott P.; Bush, Bruce L.; Hermes, Jeffrey D.; Esser, Craig K.; Hagmann, William K.; Springer, James P.; Johnson, B. V.

doi:10.1038/nsb0294-111

Cited by 169 publications

(144 citation statements)

References 48 publications

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“…The two conserved histidines of strands IV and V, His 166 and His 179, adjacent and in NOE contact on the convex side of the sheet were implicated in ligation of this zinc (Gooley et al, 1993;. From the loop joining strands I11 and IV a third histidine, His 151, was also found to coordinate this zinc on the basis of its imidazole assignments and NOES (Gooley et al, 1993(Gooley et al, , 1994. Because Asp 153 is in NOE contact with His 151 and is fully conserved, it is the best candidate to provide the fourth ligand to complete an ordinary tetrahedral coordination geometry.…”

Section: Role Of Metalmentioning

confidence: 99%

“…Reported locations include: in the active site of a neighboring protease molecule ( Lovejoy et al,3994b); in its own active site (Gooley et al, 1994); pointing away into "solution" (i.e., the crystal) Borkakoti et al, 1994;Stams et al, 1994); and along thecarboxyterminal helix C (Lovejoy et al, 1994a;Reinemer et al, 1994). Like the latter two reports, the mature N-terminus (Phe 83) of the catalytic domain of stromelysin in this NMR model runs along the surface of helix C. Reinemer et al (1994) reported that the amino group of the N-terminal phenylalanine forms a salt bridge with the fully conserved Asp 232 in neutrophil collagenase properly processed at the correct N-terminal residue to give full activity.…”

Section: Terminal Regionsmentioning

confidence: 99%

“…As stromelysin catalytic domain is most active at pH 6.0 (Ye et al, 1992), a logical choice would be to study the molecule at or near that pH, similar to the work reported by Gooley et at. (1994).…”

Section: Role Of Metalmentioning

confidence: 99%

“…The similarity of the tertiary structure of bacterial thermolysin with that of stromelysin catalytic domain has also been discussed by Gooley et al (1994). In 1995, coordinates of a few matrix metdoproteinase structural models became available.…”

Section: Comparison With Other Mmp Structuresmentioning

confidence: 99%

“…The structure of full-length porcine MMP-I shows that the C-terminal hemopexin-like domain is a four-bladed ''0 propeller" (Li et al, 1995). An NMR solution structure of stromelysin catalytic domain at pH 5.5 complexed with an N-carboxy alkyl inhibitor, N-(R-carboxy-ethyl)-a-(S)-(2-phenyl ethyl)-glycyl-Larginine-N-phenyl amide, has been published as well (Gooley et al, 1994), and has since been further refined (Protein Data Bank access code 2SRT).…”

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confidence: 99%

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Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Doren

Kurochkin

et al. 1995

Protein Science

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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 0-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 &sheet and a-helices of the catalytic domains of human stromelysin (NMR model) and human fibroblast collagenase (X-ray crystallographic model of Lovejoy B et al., 1994b, Biochemisfry 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 Si subsite, the second hydrophobic side chain is located on the opposite side of the inhibitor backbone in the hydrophobic Si surface subsite, and a third hydrophobic side chain (Pi) lies at the surface.Keywords: catalytic domain; hydroxamate; matrix metalloproteinase 3; multidimensional NMR; protein structure; stromelysinAs a member of the zinc-and calcium-dependent family of matrix metalloproteinases (MMPs), which hydrolyze the extracellular matrix, stromelysin participates in the tissue remodeling of health and disease. Regarding the shared domain structure of the MMPs, their subfamilies, specificity, transcriptional regulation, activation, and posttranslational regulation, see reviews of Woessner (1991), Matrisian (1992), Birkedal-Hansen et al. (1993), andNagase (1995). The involvement of MMPs in tissue remodeling includes that of development, tissue resorption, reproduction, angiogenesis, and wound healing, and that of sev-

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Section: Role Of Metalmentioning

confidence: 99%

Section: Terminal Regionsmentioning

confidence: 99%

Section: Role Of Metalmentioning

confidence: 99%

Section: Comparison With Other Mmp Structuresmentioning

confidence: 99%

mentioning

confidence: 99%

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Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Doren

Kurochkin

et al. 1995

Protein Science

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Fitting an inhibitor into the active site of thermolysin: A molecular dynamics case study

Wasserman

Hodge

1996

Proteins

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Structural Zinc Sites

Auld

2004

Handbook of Metalloproteins

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Structural zinc binding sites in proteins have a combination of four nitrogen, oxygen, and sulfur ligands provided by the side chains of amino acids of the protein. In marked contrast to catalytic zinc sites, no metal‐coordinated water molecule is present. There are over seven dozen representatives of structural zinc sites. While the sulfur of a cysteine is by far the preferred ligand for such sites, it is also found in combination with an imidazole nitrogen of a histidine, and/or a carboxylate oxygen from aspartate or glutamate. Of the 22 possible permutations of these 4 ligands, 8 have been observed. The ligands to these metal sites are provided by protein sequences as small as 10 amino acids and as large as 210 amino acids but the majority fall within the range of 25 to 50 amino acids. The ligands are frequently supplied from within or just before or after a β‐sheet secondary structure. The role of a structural zinc site is probably twofold. It maintains the structure of the protein in the immediate vicinity of the metal site. In this manner, it may influence enzymatic activity by providing active site residues involved in catalysis and/or affecting the chemical environment of catalytic groups through interaction with amino acids originating from within its metal‐binding spacers. However, in many cases these metal sites also affect the overall stability of the protein as judged by temperature and pH criteria.

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The NMR structure of the inhibited catalytic domain of human stromelysin–1

Cited by 169 publications

References 48 publications

Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor

Fitting an inhibitor into the active site of thermolysin: A molecular dynamics case study

Structural Zinc Sites

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