6HGV | pdb_00006hgv

Soluble epoxide hydrolase in complex with talinolol

PDB DOI: https://doi.org/10.2210/pdb6HGV/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2018-08-23 Released: 2019-07-03
Deposition Author(s): Kramer, J.S., Pogoryelov, D., Hiesinger, K., Proschak, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free:
0.203 (Depositor), 0.210 (DCC)
R-Value Work:
0.174 (Depositor), 0.180 (DCC)
R-Value Observed:
0.176 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Computer-Aided Selective Optimization of Side Activities of Talinolol.

Hiesinger, K., Kramer, J.S., Achenbach, J., Moser, D., Weber, J., Wittmann, S.K., Morisseau, C., Angioni, C., Geisslinger, G., Kahnt, A.S., Kaiser, A., Proschak, A., Steinhilber, D., Pogoryelov, D., Wagner, K., Hammock, B.D., Proschak, E.

(2019) ACS Med Chem Lett 10: 899-903

PubMed: 31223445 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.9b00075
Primary Citation of Related Structures:
6HGV, 6HGX

PubMed Abstract:
Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.

Organizational Affiliation

Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Strasse 9, D-60438 Frankfurt am Main, Germany.

Macromolecule Content

Total Structure Weight: 40.04 kDa
Atom Count: 2,825
Modelled Residue Count: 319
Deposited Residue Count: 346
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Bifunctional epoxide hydrolase 2	A	346	Homo sapiens	Mutation(s): 0 Gene Names: EPHX2 EC: 3.3.2.10 (PDB Primary Data), 3.1.3.76 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P34913 (Homo sapiens) Explore P34913 Go to UniProtKB: P34913
PHAROS: P34913 GTEx: ENSG00000120915
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P34913
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
G3Q Query on G3Q Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	R-Talinolol C₂₀ H₃₃ N₃ O₃ MXFWWQICDIZSOA-QGZVFWFLSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
G3Q	BindingDB: 6HGV	IC50: 2800 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.203 (Depositor), 0.210 (DCC)
R-Value Work: 0.174 (Depositor), 0.180 (DCC)
R-Value Observed: 0.176 (Depositor)

Space Group: I 2 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 79.73	α = 90
b = 91.88	β = 90
c = 106.05	γ = 90

Software Package:

Software Name	Purpose
XDS	data reduction
XSCALE	data scaling
PHASER	phasing
PHENIX	refinement
PDB_EXTRACT	data extraction

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2019-07-03

Deposition Author(s):

Funding Organization	Location	Grant Number
	Germany	Else Kroener Fresenius Stiftung TRIP Graduate School

Revision History (Full details and data files)

Version 1.0: 2019-07-03
Type: Initial release
Version 1.1: 2021-02-24
Changes: Derived calculations
Version 1.2: 2024-01-17
Changes: Data collection, Database references, Refinement description