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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


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Literature

Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11beta-hydroxydehydrogenase 1 (11beta-HSD1)

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.

(2011) Bioorg Med Chem Lett 21: 6693-6698

  • DOI: https://doi.org/10.1016/j.bmcl.2011.09.058
  • Primary Citation of Related Structures:  
    3TFQ

  • 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.


  • Organizational Affiliation

    Bristol-Myers Squibb Research & Development, PO Box 5400, Hopewell, NJ 08534-5400, USA. shung.wu@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1A,
B,
C [auth D],
D [auth E]
286Homo sapiensMutation(s): 2 
Gene Names: HSD11B1HSD11HSD11L
EC: 1.1.1.146
UniProt & NIH Common Fund Data Resources
Find proteins for P28845 (Homo sapiens)
Explore P28845 
Go to UniProtKB:  P28845
PHAROS:  P28845
GTEx:  ENSG00000117594 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28845
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
E [auth A],
G [auth B],
I [auth D],
K [auth E]
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
07M
Query on 07M

Download Ideal Coordinates CCD File 
F [auth A],
H [auth B],
J [auth D],
L [auth E]
8-{[(2-cyanopyridin-3-yl)methyl]sulfanyl}-6-hydroxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile
C16 H12 N4 O2 S
RMZOHPFYZBRDJW-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
M [auth E]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
07M Binding MOAD:  3TFQ IC50: 12 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.5α = 90
b = 94β = 90
c = 167.8γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2011-11-02 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-02
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations