3D5Q

Crystal Structure of 11b-HSD1 in Complex with Triazole Inhibitor

Summary for 3D5Q

• Entry DOI: 10.2210/pdb3d5q/pdb
• Related: 3CZR 3D3E 3D4N
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-[1-(4-fluorophenyl)cyclopropyl]-4-(1-methylethyl)-5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazole (3 entities in total)
• Functional Keywords: oxidoreductase, 11beta, hydroxysteroid, dehydrogenase, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, microsome, nadp, polymorphism, signal-anchor, steroid metabolism, transmembrane
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane; Single-pass type II membrane protein: P28845
• Total number of polymer chains: 4
• Total formula weight: 124510.60

Authors

Wang, Z.,Liu, J.,Sudom, A.,Walker, N.P.C. (deposition date: 2008-05-16, release date: 2008-10-07, Last modification date: 2024-02-21)

Primary citation

Tu, H.,Powers, J.P.,Liu, J.,Ursu, S.,Sudom, A.,Yan, X.,Xu, H.,Meininger, D.,Degraffenreid, M.,He, X.,Jaen, J.C.,Sun, D.,Labelle, M.,Yamamoto, H.,Shan, B.,Walker, N.P.,Wang, Z.
Distinctive molecular inhibition mechanisms for selective inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.
Bioorg.Med.Chem., 16:8922-8931, 2008

PubMed Abstract: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.

PubMed: 18789704
DOI: 10.1016/j.bmc.2008.08.065

Experimental method

X-RAY DIFFRACTION (2.55 Å)