3TFQ

Crystal structure of 11b-hsd1 double mutant (l262r, f278e) complexed with 8-{[(2-CYANOPYRIDIN-3-YL)METHYL]SULFANYL}-6-HYDROXY-3,4-DIHYDRO-1H-PYRANO[3,4-C]PYRIDINE-5-CARBONITRILE

Summary for 3TFQ

• Entry DOI: 10.2210/pdb3tfq/pdb
• Related: 3CH6
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 8-{[(2-cyanopyridin-3-yl)methyl]sulfanyl}-6-hydroxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile, ... (5 entities in total)
• Functional Keywords: 11b-hsd1, sdr, dehydrogenase, hydroxysteroid, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 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: 129748.53

Authors

Sheriff, S. (deposition date: 2011-08-16, release date: 2011-11-02, Last modification date: 2024-04-03)

Primary citation

Wu, S.C.,Yoon, D.,Chin, J.,van Kirk, K.,Seethala, R.,Golla, R.,He, B.,Harrity, T.,Kunselman, L.K.,Morgan, N.N.,Ponticiello, R.P.,Taylor, J.R.,Zebo, R.,Harper, T.W.,Li, W.,Wang, M.,Zhang, L.,Sleczka, B.G.,Nayeem, A.,Sheriff, S.,Camac, D.M.,Morin, P.E.,Everlof, J.G.,Li, Y.X.,Ferraro, C.A.,Kieltyka, K.,Shou, W.,Vath, M.B.,Zvyaga, T.A.,Gordon, D.A.,Robl, J.A.
Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11beta-hydroxydehydrogenase 1 (11beta-HSD1)
Bioorg.Med.Chem.Lett., 21:6693-6698, 2011

PubMed Abstract: Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.

PubMed: 21983444
DOI: 10.1016/j.bmcl.2011.09.058

Experimental method

X-RAY DIFFRACTION (1.8 Å)