5HA7

Human Aldose Reductase in Complex with NADP+ and WY14643 in Space Group P212121

PDB DOI: https://doi.org/10.2210/pdb5HA7/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21
Mutation(s): Yes

Deposited: 2015-12-30 Released: 2016-09-28
Deposition Author(s): Sawaya, M.R., Cascio, D., Balendiran, G.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.65 ?
R-Value Free: 0.195
R-Value Work: 0.168
R-Value Observed: 0.169

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

Characterization of WY 14,643 and its Complex with Aldose Reductase.

Sawaya, M.R., Verma, M., Balendiran, V., Rath, N.P., Cascio, D., Balendiran, G.K.

(2016) Sci Rep 6: 34394-34394

PubMed: 27721416 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/srep34394
Primary Citation of Related Structures:
5HA7

PubMed Abstract:
The peroxisome proliferator, WY 14,643 exhibits a pure non-competitive inhibition pattern in the aldehyde reduction and in alcohol oxidation activities of human Aldose reductase (hAR). Fluorescence emission measurements of the equilibrium dissociation constants, K _d, of oxidized (hAR?NADP ⁺) and reduced (hAR?NADPH) holoenzyme complexes display a 2-fold difference between them. K _d values for the dissociation of WY 14,643 from the oxidized (hAR?NADP ⁺?WY 14,643) and reduced (hAR?NADPH?WY 14,643) ternary complexes are comparable to each other. The ternary complex structure of hAR?NADP ⁺?WY 14,643 reveals the first structural evidence of a fibrate class drug binding to hAR. These observations demonstrate how fibrate molecules such as WY 14,643, besides being valued as agonists for PPAR, also inhibit hAR.

Organizational Affiliation

UCLA-DOE, 611 Charles E. Young Drive East, 220 Boyer Hall, Los Angeles, CA 90095, USA.

Macromolecule Content

Total Structure Weight: 74.7 kDa
Atom Count: 5,846
Modelled Residue Count: 632
Deposited Residue Count: 632
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Aldose reductase	A, B	316	Homo sapiens	Mutation(s): 1 Gene Names: AKR1B1, ALDR1 EC: 1.1.1.21 (PDB Primary Data), 1.1.1.372 (UniProt), 1.1.1.300 (UniProt), 1.1.1.54 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P15121 (Homo sapiens) Explore P15121 Go to UniProtKB: P15121
PHAROS: P15121 GTEx: ENSG00000085662
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P15121
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 I [auth B] SDF format, chain C [auth A] MOL2 format, chain I [auth B] MOL2 format, chain C [auth A] mmCIF format, chain I [auth B] mmCIF format, chain C [auth A]	C [auth A], I [auth B]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain C [auth A] Focus chain I [auth B] Interactions & Density Focus chain C [auth A] Focus chain I [auth B]
WY1 Query on WY1 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain J [auth B] MOL2 format, chain D [auth A] MOL2 format, chain J [auth B] mmCIF format, chain D [auth A] mmCIF format, chain J [auth B]	D [auth A], J [auth B]	2-({4-CHLORO-6-[(2,3-DIMETHYLPHENYL)AMINO]PYRIMIDIN-2-YL}SULFANYL)ACETIC ACID C₁₄ H₁₄ Cl N₃ O₂ S SZRPDCCEHVWOJX-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain J [auth B] Interactions & Density Focus chain D [auth A] Focus chain J [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain N [auth B] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] MOL2 format, chain H [auth A] MOL2 format, chain N [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] mmCIF format, chain H [auth A] mmCIF format, chain N [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B]	E [auth A] F [auth A] G [auth A] H [auth A] K [auth B] E [auth A], F [auth A], G [auth A], H [auth A], K [auth B], L [auth B], M [auth B], N [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.65 ?
R-Value Free: 0.195
R-Value Work: 0.168
R-Value Observed: 0.169
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 83.306	α = 90
b = 85.917	β = 90
c = 104.37	γ = 90

Software Package:

Software Name	Purpose
Aimless	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction
autoPROC	data scaling
REFMAC	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-09-28

Deposition Author(s):

Sawaya, M.R.

Cascio, D.

Balendiran, G.K.

Revision History (Full details and data files)

Version 1.0: 2016-09-28
Type: Initial release
Version 1.1: 2016-10-26
Changes: Database references
Version 1.2: 2017-11-22
Changes: Derived calculations, Refinement description
Version 1.3: 2023-09-27
Changes: Data collection, Database references, Refinement description

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Help and Resources

5HA7

Human Aldose Reductase in Complex with NADP+ and WY14643 in Space Group P212121

Characterization of WY 14,643 and its Complex with Aldose Reductase.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)