X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity

Alexander G. Pavlovsky, Mark G. Williams, Qizhuang Ye, Daniel F. Ortwine, Claude F. Purchase, Andrew D. White, V. Dhanaraj, Bruce D. Roth, Linda L. Johnson, Donald Hupe, Christine Humblet, Tom L. Blundell

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 Å. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S1/' pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S1/' pocket. The largest differences occur in the loop forming the 'top' of this pocket. The occupation of these nonpeptidic inhibitors in the S1/' pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.

Original languageEnglish (US)
Pages (from-to)1455-1462
Number of pages8
JournalProtein Science
Volume8
Issue number7
StatePublished - 1999
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 3
Matrix Metalloproteinase Inhibitors
Catalytic Domain
X-Rays
X rays
Matrix Metalloproteinases
Peptides
Occupations
Crystal structure
Connective Tissue
Biological Availability
Multiple Sclerosis
Arthritis
Tissue
Substrates
Enzymes
Neoplasms

Keywords

  • Drug design
  • Matrix metalloproteinase
  • MMP-3
  • Nonpeptide inhibitors
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry

Cite this

Pavlovsky, A. G., Williams, M. G., Ye, Q., Ortwine, D. F., Purchase, C. F., White, A. D., ... Blundell, T. L. (1999). X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity. Protein Science, 8(7), 1455-1462.

X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors : Implications for inhibitor selectivity. / Pavlovsky, Alexander G.; Williams, Mark G.; Ye, Qizhuang; Ortwine, Daniel F.; Purchase, Claude F.; White, Andrew D.; Dhanaraj, V.; Roth, Bruce D.; Johnson, Linda L.; Hupe, Donald; Humblet, Christine; Blundell, Tom L.

In: Protein Science, Vol. 8, No. 7, 1999, p. 1455-1462.

Research output: Contribution to journalArticle

Pavlovsky, AG, Williams, MG, Ye, Q, Ortwine, DF, Purchase, CF, White, AD, Dhanaraj, V, Roth, BD, Johnson, LL, Hupe, D, Humblet, C & Blundell, TL 1999, 'X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity', Protein Science, vol. 8, no. 7, pp. 1455-1462.
Pavlovsky, Alexander G. ; Williams, Mark G. ; Ye, Qizhuang ; Ortwine, Daniel F. ; Purchase, Claude F. ; White, Andrew D. ; Dhanaraj, V. ; Roth, Bruce D. ; Johnson, Linda L. ; Hupe, Donald ; Humblet, Christine ; Blundell, Tom L. / X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors : Implications for inhibitor selectivity. In: Protein Science. 1999 ; Vol. 8, No. 7. pp. 1455-1462.
@article{683b98c6b297445c928d8ec7cbf4e371,
title = "X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity",
abstract = "Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 {\AA}. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S1/' pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S1/' pocket. The largest differences occur in the loop forming the 'top' of this pocket. The occupation of these nonpeptidic inhibitors in the S1/' pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.",
keywords = "Drug design, Matrix metalloproteinase, MMP-3, Nonpeptide inhibitors, X-ray crystallography",
author = "Pavlovsky, {Alexander G.} and Williams, {Mark G.} and Qizhuang Ye and Ortwine, {Daniel F.} and Purchase, {Claude F.} and White, {Andrew D.} and V. Dhanaraj and Roth, {Bruce D.} and Johnson, {Linda L.} and Donald Hupe and Christine Humblet and Blundell, {Tom L.}",
year = "1999",
language = "English (US)",
volume = "8",
pages = "1455--1462",
journal = "Protein Science",
issn = "0961-8368",
publisher = "Cold Spring Harbor Laboratory Press",
number = "7",

}

TY - JOUR

T1 - X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors

T2 - Implications for inhibitor selectivity

AU - Pavlovsky, Alexander G.

AU - Williams, Mark G.

AU - Ye, Qizhuang

AU - Ortwine, Daniel F.

AU - Purchase, Claude F.

AU - White, Andrew D.

AU - Dhanaraj, V.

AU - Roth, Bruce D.

AU - Johnson, Linda L.

AU - Hupe, Donald

AU - Humblet, Christine

AU - Blundell, Tom L.

PY - 1999

Y1 - 1999

N2 - Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 Å. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S1/' pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S1/' pocket. The largest differences occur in the loop forming the 'top' of this pocket. The occupation of these nonpeptidic inhibitors in the S1/' pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.

AB - Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 Å. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S1/' pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S1/' pocket. The largest differences occur in the loop forming the 'top' of this pocket. The occupation of these nonpeptidic inhibitors in the S1/' pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.

KW - Drug design

KW - Matrix metalloproteinase

KW - MMP-3

KW - Nonpeptide inhibitors

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=0032776835&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032776835&partnerID=8YFLogxK

M3 - Article

C2 - 10422833

AN - SCOPUS:0032776835

VL - 8

SP - 1455

EP - 1462

JO - Protein Science

JF - Protein Science

SN - 0961-8368

IS - 7

ER -