4JII

Crystal Structure Of AKR1B10 Complexed With NADP+ And Zopolrestat

PDB DOI: https://doi.org/10.2210/pdb4JII/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21
Mutation(s): No

Deposited: 2013-03-06 Released: 2013-10-23
Deposition Author(s): Zhang, L., Zheng, X., Zhang, H., Zhao, Y., Chen, K., Zhai, J., Hu, X., Structural Genomics Consortium (SGC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.20 Å
R-Value Free: 0.218
R-Value Work: 0.172
R-Value Observed: 0.172

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Inhibitor selectivity between aldo-keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111).

Zhang, L., Zhang, H., Zhao, Y., Li, Z., Chen, S., Zhai, J., Chen, Y., Xie, W., Wang, Z., Li, Q., Zheng, X., Hu, X.

(2013) FEBS Lett 587: 3681-3686

PubMed: 24100137 Search on PubMed
DOI: https://doi.org/10.1016/j.febslet.2013.09.031
Primary Citation of Related Structures:
4GQG, 4I5X, 4JIH, 4JII, 4JIR

PubMed Abstract:
The antineoplastic target aldo-keto reductase family member 1B10 (AKR1B10) and the critical polyol pathway enzyme aldose reductase (AKR1B1) share high structural similarity. Crystal structures reported here reveal a surprising Trp112 native conformation stabilized by a specific Gln114-centered hydrogen bond network in the AKR1B10 holoenzyme, and suggest that AKR1B1 inhibitors could retain their binding affinities toward AKR1B10 by inducing Trp112 flip to result in an "AKR1B1-like" active site in AKR1B10, while selective AKR1B10 inhibitors can take advantage of the broader active site of AKR1B10 provided by the native Trp112 side-chain orientation.

Organizational Affiliation

School of Pharmaceutical Sciences, Centre for Cellular and Structural Biology of Sun Yat-sen University, Guangzhou 510006, China.

Macromolecule Content

Total Structure Weight: 37.48 kDa
Atom Count: 2,817
Modelled Residue Count: 318
Deposited Residue Count: 318
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Aldo-keto reductase family 1 member B10	A [auth X]	318	Homo sapiens	Mutation(s): 0 Gene Names: AKR1B10, AKR1B11 EC: 1.1.1 (PDB Primary Data), 1.1.1.300 (UniProt), 1.1.1.54 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for O60218 (Homo sapiens) Explore O60218 Go to UniProtKB: O60218
PHAROS: O60218 GTEx: ENSG00000198074
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O60218
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAP Query on NAP Download Ideal Coordinates CCD File SDF format, chain B [auth X] MOL2 format, chain B [auth X] mmCIF format, chain B [auth X]	B [auth X]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain B [auth X] Interactions & Density Focus chain B [auth X]
ZST Query on ZST Download Ideal Coordinates CCD File SDF format, chain C [auth X] MOL2 format, chain C [auth X] mmCIF format, chain C [auth X]	C [auth X]	3,4-DIHYDRO-4-OXO-3-((5-TRIFLUOROMETHYL-2-BENZOTHIAZOLYL)METHYL)-1-PHTHALAZINE ACETIC ACID C₁₉ H₁₂ F₃ N₃ O₃ S BCSVCWVQNOXFGL-UHFFFAOYSA-N		Interactions Focus chain C [auth X] Interactions & Density Focus chain C [auth X]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain D [auth X] MOL2 format, chain D [auth X] mmCIF format, chain D [auth X]	D [auth X]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain D [auth X] Interactions & Density Focus chain D [auth X]

Binding Affinity Annotations
ID	Source	Binding Affinity
ZST	BindingDB: 4JII	IC50: min: 620, max: 2360 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.20 Å
R-Value Free: 0.218
R-Value Work: 0.172
R-Value Observed: 0.172
Space Group: P 6₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 90.002	α = 90
b = 90.002	β = 90
c = 78.552	γ = 120

Software Package:

Software Name	Purpose
CrysalisPro	data collection
MOLREP	phasing
PHENIX	refinement
CrysalisPro	data reduction
SCALA	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-10-23

Deposition Author(s):

Structural Genomics Consortium (SGC)

Revision History (Full details and data files)

Version 1.0: 2013-10-23
Type: Initial release
Version 1.1: 2013-11-27
Changes: Database references
Version 1.2: 2018-01-24
Changes: Structure summary
Version 1.3: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description