3D3E

Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) in Complex with Benzamide Inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 

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Literature

Discovery of Novel, Potent Benzamide Inhibitors of 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model

Julian, L.D., Wang, Z., Bostick, T., Caille, S., Choi, R., Degraffenreid, M., Di, Y., He, X., Hungate, R.W., Jaen, J.C., Liu, J., Monshouwer, M., McMinn, D., Rew, Y., Sudom, A., Sun, D., Tu, H., Ursu, S., Walker, N., Yan, X., Ye, Q., Powers, J.P.

(2008) J Med Chem 51: 3953-3960

  • DOI: https://doi.org/10.1021/jm800310g
  • Primary Citation of Related Structures:  
    3D3E, 3D4N

  • PubMed Abstract: 

    We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.

    • Organizational Affiliation: 

    Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. ljulian@amgen.com


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1
A, B, C, D
286Homo sapiensMutation(s): 1 
Gene Names: HSD11B1, HSD11, HSD11L
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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
D3E BindingDB:  3D3E IC50: min: 1.4, max: 124 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.7α = 90
b = 152.846β = 92.11
c = 73.708γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-07-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations, Source and taxonomy
  • Version 1.3: 2023-08-30
    Changes: Data collection, Refinement description