Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity.
The binding of two 5-substituted-1,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (P1-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-155 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzyme/inhibitor complexes, the S1' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity.
Finzel
B C
BC
Structural, Analytical & Medicinal Chemistry, Pharmacia and Upjohn, Kalamazoo, Michigan 49007, USA. Barry.C.Finzel@am.pnu.com
Baldwin
E T
ET
Bryant
G L
GL
Hess
G F
GF
Wilks
J W
JW
Trepod
C M
CM
Mott
J E
JE
Marshall
V P
VP
Petzold
G L
GL
Poorman
R A
RA
O'Sullivan
T J
TJ
Schostarez
H J
HJ
Mitchell
M A
MA
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D017364:Collagenases / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014714:Vertebrates; D015032:Zinc / Q000737:chemistry
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C116490:PNU 141803; C116491:PNU 142372; D013830:Thiadiazoles; D014508:Urea; D017364:Collagenases; D015032:Zinc