Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase.
The X-ray crystal structure of the proform of human matrix metalloproteinase MMP9 has been solved to 2.5 A resolution. The construct includes the prodomain, the catalytic domain and three FnII (fibronectin type II) domains. The prodomain is inserted into the active-site cleft, blocking access to the catalytic zinc. Comparison with the crystal structure of the most closely related MMP, MMP2, indicates that the conformations of residues in the active-site cleft and in the cysteine-switch peptide of the prodomain are highly conserved and that design of MMP9-specific inhibitors will be challenging. In common with MMP2, the MMP9 S1' inhibitor-binding pocket is large compared with that of other MMPs. One small point of difference in the S1' binding pockets of MMP9 and MMP2 may provide an opportunity to explore the design of specific inhibitors. The side chain of Arg424 in MMP9 is angled slightly away from the S1' pocket when compared with the corresponding residue in MMP2, Thr424. The secondary structure of the FnII domains is conserved between the two closely related MMPs, although the second FnII domain makes no contact with the catalytic domain in MMP9, while the same domain in MMP2 has a substantial area of interaction with the catalytic domain.
Elkins
Patricia A
PA
GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. patricia_a_elkins@gsk.com
Ho
Yen Sen
YS
Smith
Ward W
WW
Janson
Cheryl A
CA
D'Alessio
Karla J
KJ
McQueney
Michael S
MS
Cummings
Maxwell D
MD
Romanic
Anne M
AM
D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D003001:Cloning, Molecular; D017364:Collagenases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D004792:Enzyme Precursors / Q000737:chemistry*; D004926:Escherichia coli / Q000378:metabolism; D005780:Gelatin / Q000737:chemistry*; D006801:Humans; D020780:Matrix Metalloproteinase 9; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D004792:Enzyme Precursors; D010455:Peptides; D005780:Gelatin; D001120:Arginine; D017364:Collagenases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9