title: X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily.
abstract: BACKGROUND
  Stromelysin belongs to a family of zinc-dependent endopeptidases referred to as matrix metalloproteinases (MMPs, matrixins) because of their capacity for selective degradation of various components of the extracellular matrix. Matrixins play key roles in diseases as diverse as arthritis and cancer and hence are important targets for therapeutic intervention.
  
  
  RESULTS
  The crystal structure of the stromelysin catalytic domain (SCD) with bound hydroxamate inhibitor, solved by multiple isomorphous replacement, shows deep S1' specificity pocket which explains differences in inhibitors binding between the collagenases and stromelysin. The binding of calcium ions by loops at the two ends of a beta-strand which marks the boundary of the active site provides a structural rationale for the importance of these cations for stability and catalytic activity. Major differences between the matrixins are clustered in two regions forming the entrance to the active site and hence may be determinants of substrate selectivity.
  
  
  CONCLUSIONS
  Structural comparisons of SCD with representative members of the metalloproteinase superfamily clearly highlight the conservation of key secondary structural elements, in spite of major variations in the sequences including insertions and deletions of functional domains. However, the three-dimensional structure of SCD, which is generally closely related to the collagenases, shows significant differences not only in the peripheral regions but also in the specificity pockets; these latter differences should facilitate the rational design of specific inhibitors.
authors: Department of Crystallography, Birkbeck College, London, UK.
authors: V
authors: V
authors: Dhanaraj
authors: Q Z
authors: QZ
authors: Ye
authors: L L
authors: LL
authors: Johnson
authors: D J
authors: DJ
authors: Hupe
authors: D F
authors: DF
authors: Ortwine
authors: J B
authors: JB
authors: Dunbar
authors: J R
authors: JR
authors: Rubin
authors: A
authors: A
authors: Pavlovsky
authors: C
authors: C
authors: Humblet
authors: T L
authors: TL
authors: Blundell
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017364:Collagenases / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C102803:PD 140798; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; C071288:astacin; C095666:serralysin; C028220:Crotalus adamanteus proteinase II; D015032:Zinc