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Solution structures of stromelysin complexed to thiadiazole inhibitors
Author(s) -
Stockman Brian J.,
Waldon Daniel J.,
Gates Jo A.,
Scahill Terrence A.,
Kloosterman David A.,
Mizsak Stephen A.,
Jacobsen E. Jon,
Belonga Kenneth L.,
Mitchell Mark A.,
Mao Boryeu,
Petke James D.,
Goodman Linda,
Powers Elaine A.,
Ledbetter Steven R.,
Kaytes Paul S.,
Vogeli Gabriel,
Marshall Vincent P.,
Petzold Gary L.,
Poorman Roger A.
Publication year - 1998
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.5560071105
Subject(s) - chemistry , ring (chemistry) , matrix metalloproteinase , stereochemistry , protonation , matrix metalloproteinase inhibitor , nuclear magnetic resonance spectroscopy , ligand (biochemistry) , active site , enzyme , biochemistry , organic chemistry , receptor , ion
Unregulated or overexpressed matrix metalloproteinases (MMPs), including stromelysin, collagenase, and gelatinase, have been implicated in several pathological conditions including arthritis and cancer. Small‐molecule MMP inhibitors may have therapeutic value in the treatment of these diseases. In this regard, the solution structures of two stromelysin/inhibitor complexes have been investigated using H, 13 C, and 15 N NMR spectroscopy. Both inhibitors are members of a novel class of matrix metalloproteinase inhibitor that contain a thiadiazole group and that interact with stromelysin in a manner distinct from other classes of inhibitors. The inhibitors coordinate the catalytic zinc atom through their exocyclic sulfur atom, with the remainder of the ligand extending into the S1‐S3 side of the active site. The binding of inhibitor containing a protonated or fluorinated aromatic ring was investigated using H and 19 F NMR spectroscopy. The fluorinated ring was found to have a reduced ring‐flip rate compared to the protonated version. A strong, coplanar interaction between the fluorinated ring of the inhibitor and the aromatic ring of Tyr155 is proposed to account for the reduced ring‐flip rate and for the increase in binding affinity observed for the fluorinated inhibitor compared to the protonated inhibitor. Binding interactions observed for the thiadiazole class of ligands have implications for the design of matrix metalloproteinase inhibitors.