Original scientific paper

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

Venugopal Dhanaraj ; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
Mark G. Williams ; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
Qi-Zhuang Ye ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Franck Molina ; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
Linda L. Johnson ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Daniel F. Ortwine ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Alexander Pavlovsky ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
J. Ron Rubin ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Richard W. Skeean ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Andy D. White ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Christine Humblet ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Donald J. Hupe ; Departments of Biochemistry and Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
Tom L. Blundell ; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK

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.

Keywords

inhibitor; matrixin; matrix metalloproteinase-3 (MMP-3); stromelysin-1; MMP-2; gelatinase A; metzincin

Hrčak ID:

132246

URI

https://hrcak.srce.hr/132246

Publication date:

1.9.1999.

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