X-ray crystal structure of human heme oxygenase-1 with (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-trifluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane: a novel, inducible binding mode.
The crystal structure of human heme oxygenase-1 (HO-1) in complex with (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-trifluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane (4) reveals a novel, inducible binding mode. Inhibitor 4 coordinates the heme iron, with its chlorophenyl group bound in a distal hydrophobic pocket, as seen in previous structures. However, accommodation of the 5-trifluoromethylpyridin-2-yl group requires a significant shift in the proximal helix, inducing the formation of a hydrophobic pocket. This is the first example of an induced binding pocket observed in HO-1.
Rahman
Mona N
MN
Department of Biochemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
Vlahakis
Jason Z
JZ
Vukomanovic
Dragic
D
Szarek
Walter A
WA
Nakatsu
Kanji
K
Jia
Zongchao
Z
D018360:Crystallography, X-Ray; D004148:Dioxolanes / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions
C543612:(2R,4S)-2-(2-(4-chlorophenyl)ethyl)-2-((1H-imidazol-1-yl)methyl)-4(((5-trifluoromethylpyridin-2-yl)thio)methyl)-1,3-dioxolane; D004148:Dioxolanes; D004791:Enzyme Inhibitors; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1