X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor

Venugopal Dhanaraj, Mark G. Williams, Qizhuang Ye, Franck Molina, Linda L. Johnson, Daniel F. Ortwine, Alexander Pavlovsky, J. Ron Rubin, Richard W. Skeean, Andy D. White, Christine Humblet, Donald J. Hupe, Tom L. Blundell

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Gelatinase A is a key enzyme in the family of matrix metalloproteinases (matrixins) that are involved in the degradation of the extracellular matrix. As this process is an integral part of tumour cell metastasis and angiogenesis, gelatinase is an important target for therapeutic intervention. The X-ray crystal structure of the gelatinase A catalytic domain (GaCD) complexed with batimastat (BB94), a hydroxamate inhibitor, shows an active site with a large S1' specificity pocket. The structure is similar to previously solved structures of stromelysin catalytic domain (SCD) but with differences in VR1 and VR2, two surface-exposed loops on either side of the entrance to the active site. Comparison of GaCD with other members of the matrix metalloproteinase (MMP) family highlights the conservation of key secondary structural elements and the significant differences in the specificity pockets, knowledge of which should enhance our ability to design specific inhibitors for this important anticancer target.

Original languageEnglish (US)
Pages (from-to)575-591
Number of pages17
JournalCroatica Chemica Acta
Volume72
Issue number2-3
StatePublished - Sep 1999
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 2
Matrix Metalloproteinases
X rays
Matrix Metalloproteinase 3
Gelatinases
Tumors
Conservation
Crystal structure
Cells
Degradation
Enzymes

Keywords

  • Gelatinase A
  • Inhibitor
  • Matrix metalloproteinase-3 (MMP-3)
  • Matrixin
  • Metzincin
  • MMP-2
  • Stromelysin-1

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Dhanaraj, V., Williams, M. G., Ye, Q., Molina, F., Johnson, L. L., Ortwine, D. F., ... Blundell, T. L. (1999). X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor. Croatica Chemica Acta, 72(2-3), 575-591.

X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor. / Dhanaraj, Venugopal; Williams, Mark G.; Ye, Qizhuang; Molina, Franck; Johnson, Linda L.; Ortwine, Daniel F.; Pavlovsky, Alexander; Rubin, J. Ron; Skeean, Richard W.; White, Andy D.; Humblet, Christine; Hupe, Donald J.; Blundell, Tom L.

In: Croatica Chemica Acta, Vol. 72, No. 2-3, 09.1999, p. 575-591.

Research output: Contribution to journalArticle

Dhanaraj, V, Williams, MG, Ye, Q, Molina, F, Johnson, LL, Ortwine, DF, Pavlovsky, A, Rubin, JR, Skeean, RW, White, AD, Humblet, C, Hupe, DJ & Blundell, TL 1999, 'X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor', Croatica Chemica Acta, vol. 72, no. 2-3, pp. 575-591.
Dhanaraj V, Williams MG, Ye Q, Molina F, Johnson LL, Ortwine DF et al. X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor. Croatica Chemica Acta. 1999 Sep;72(2-3):575-591.
Dhanaraj, Venugopal ; Williams, Mark G. ; Ye, Qizhuang ; Molina, Franck ; Johnson, Linda L. ; Ortwine, Daniel F. ; Pavlovsky, Alexander ; Rubin, J. Ron ; Skeean, Richard W. ; White, Andy D. ; Humblet, Christine ; Hupe, Donald J. ; Blundell, Tom L. / X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor. In: Croatica Chemica Acta. 1999 ; Vol. 72, No. 2-3. pp. 575-591.
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AB - Gelatinase A is a key enzyme in the family of matrix metalloproteinases (matrixins) that are involved in the degradation of the extracellular matrix. As this process is an integral part of tumour cell metastasis and angiogenesis, gelatinase is an important target for therapeutic intervention. The X-ray crystal structure of the gelatinase A catalytic domain (GaCD) complexed with batimastat (BB94), a hydroxamate inhibitor, shows an active site with a large S1' specificity pocket. The structure is similar to previously solved structures of stromelysin catalytic domain (SCD) but with differences in VR1 and VR2, two surface-exposed loops on either side of the entrance to the active site. Comparison of GaCD with other members of the matrix metalloproteinase (MMP) family highlights the conservation of key secondary structural elements and the significant differences in the specificity pockets, knowledge of which should enhance our ability to design specific inhibitors for this important anticancer target.

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