2J14

3,4,5-Trisubstituted Isoxazoles as Novel PPARdelta Agonists: Part2

PDB DOI: https://doi.org/10.2210/pdb2J14/pdb

Classification: TRANSCRIPTION
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2006-08-08 Released: 2006-09-06
Deposition Author(s): Epple, R., Azimioara, M., Russo, R., Xie, Y., Wang, X., Cow, C., Wityak, J., Karanewsky, D., Bursulaya, B., Kreusch, A., Tuntland, T., Gerken, A., Iskandar, M., Saez, E., Seidel, H.M., Tian, S.S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.284
R-Value Work: 0.224
R-Value Observed: 0.224

wwPDB Validation 3D Report Full Report

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

Literature

3,4,5-Trisubstituted Isoxazoles as Novel Ppardelta Agonists. Part 2

Epple, R., Azimioara, M., Russo, R., Xie, Y., Wang, X., Cow, C., Wityak, J., Karanewsky, D., Bursulaya, B., Kreusch, A., Tuntland, T., Gerken, A., Iskandar, M., Saez, E., Seidel, H.M., Tian, S.S.

(2006) Bioorg Med Chem Lett 16: 5488

PubMed: 16931011 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2006.08.052
Primary Citation of Related Structures:
2J14

PubMed Abstract:
A series of PPARdelta-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARdelta agonist with good in vivo PK properties in mouse (C(max)=5.1 microM, t(1/2)=3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARdelta is discussed.

Organizational Affiliation

Department of Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. repple@gnf.org

Macromolecule Content

Total Structure Weight: 66.38 kDa
Atom Count: 4,273
Modelled Residue Count: 506
Deposited Residue Count: 570
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DELTA	A, B	285	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for Q03181 (Homo sapiens) Explore Q03181 Go to UniProtKB: Q03181
PHAROS: Q03181 GTEx: ENSG00000112033
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q03181
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
GNI Query on GNI Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth B]	C [auth A], D [auth B]	(3-{4-[2-(2,4-DICHLORO-PHENOXY)-ETHYLCARBAMOYL]-5-PHENYL-ISOXAZOL-3-YL}-PHENYL)-ACETIC ACID C₂₆ H₂₀ Cl₂ N₂ O₅ HINPKGVWVQYESB-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
GNI	BindingDB: 2J14	EC50: 70 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.284
R-Value Work: 0.224
R-Value Observed: 0.224
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 39.376	α = 90
b = 93.39	β = 90
c = 92.258	γ = 90

Software Package:

Software Name	Purpose
CNS	refinement
DENZO	data reduction
SCALEPACK	data scaling
MOLREP	phasing

Structure Validation

View Full Validation Report

Entry History

Deposition Data

Released Date: 2006-09-06

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2006-09-06
Type: Initial release
Version 1.1: 2011-05-08
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Version format compliance
Version 1.3: 2023-12-13
Changes: Data collection, Database references, Refinement description