3D3E

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

PDB DOI: https://doi.org/10.2210/pdb3D3E/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2008-05-09 Released: 2008-07-01
Deposition Author(s): Wang, Z., Sudom, A., Liu, J., Walker, N.P.

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

Starting Model: experimental
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Ligand Structure Quality Assessment

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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

PubMed: 18553955 Search on PubMed
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. [email protected]

Macromolecule Content

Total Structure Weight: 132.05 kDa
Atom Count: 8,318
Modelled Residue Count: 1,039
Deposited Residue Count: 1,144
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Corticosteroid 11-beta-dehydrogenase isozyme 1	A, B, C, D	286	Homo sapiens	Mutation(s): 1 Gene Names: HSD11B1, HSD11, HSD11L EC: 1.1.1.146 (PDB Primary Data), 1.1.1.201 (UniProt)
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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P28845
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAP Query on NAP Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain I [auth C] SDF format, chain K [auth D] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] MOL2 format, chain K [auth D] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B] mmCIF format, chain I [auth C] mmCIF format, chain K [auth D]	E [auth A], G [auth B], I [auth C], K [auth D]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D]
D3E Query on D3E Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain J [auth C] SDF format, chain L [auth D] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain J [auth C] MOL2 format, chain L [auth D] mmCIF format, chain F [auth A] mmCIF format, chain H [auth B] mmCIF format, chain J [auth C] mmCIF format, chain L [auth D]	F [auth A], H [auth B], J [auth C], L [auth D]	N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamide C₂₄ H₂₇ F₃ N₂ O₂ FLRYWTWLHWACRP-GRWTVWFQSA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D] Interactions & Density Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D]

Binding Affinity Annotations
ID	Source	Binding 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 = 56.7	α = 90
b = 152.846	β = 92.11
c = 73.708	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2008-07-01

Deposition Author(s):

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