Designing inhibitors of the metalloproteinase superfamily: comparative analysis of representative structures.
Structural comparisons of representative members of the zinc metalloproteinase superfamily show that the key secondary structural elements are conserved, in spite of major variations in the sequences including insertions and deletions of functional domains. Major differences between the matrix metalloproteinases (matrixins) are clustered in two regions forming the entrance to the active site and hence may be determinants of substrate selectivity. A comparison of the structures of matrixin-inhibitor complexes shows that there are significant differences even among the closely related matrixins, not only in the peripheral regions but also in the specificity pockets; these differences offer an excellent opportunity for the design of specific inhibitors targetted to individual members.
Dhanaraj
V
V
Department of Crystallography, Birkbeck College, London, UK.
Ye
Q Z
QZ
Johnson
L L
LL
Hupe
D J
DJ
Ortwine
D F
DF
Dunbar
J B
JB
Rubin
J R
JR
Pavlovsky
A
A
Humblet
C
C
Blundell
T L
TL
D001665:Binding Sites; D002384:Catalysis; D017364:Collagenases / Q000737:chemistry; D015195:Drug Design; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013820:Thermolysin / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; C071288:astacin; D013820:Thermolysin; C095666:serralysin; C028220:Crotalus adamanteus proteinase II; D015032:Zinc