PDBsum entry 5hjs

Signaling protein

PDB id: 5hjs

Contents

Protein chains

226 a.a.

15 a.a.

Ligands

668 ×2

SO4 ×2

Waters ×328

PDB id:

5hjs

Name:

Signaling protein

Title:

Identification of lxrbeta selective agonists for the treatment of alzheimer's disease

Structure:

Oxysterols receptor lxr-alpha. Chain: a, b. Synonym: liver x receptor alpha,nuclear receptor subfamily 1 group h member 3. Engineered: yes. Nuclear receptor coactivator 1. Chain: c, d. Synonym: ncoa-1,class e basic helix-loop-helix protein 74,bhlhe74, protein hin-2,rip160,renal carcinoma antigen ny-ren-52,steroid

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1h3, lxra. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.72Å R-factor: 0.210 R-free: 0.238

Authors:

G.Parthasarathy,D.Klein

Key ref:

S.J.Stachel et al. (2016). Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's Disease. J Med Chem, 59, 3489-3498. PubMed id: 27011007 DOI: 10.1021/acs.jmedchem.6b00176

Date:

13-Jan-16 Release date: 06-Apr-16

Protein chains

Q13133  (NR1H3_HUMAN) -  Oxysterols receptor LXR-alpha from Homo sapiens

Seq: 447 a.a.

Struc: 226 a.a.

Protein chains

Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1 from Homo sapiens

Seq: 1441 a.a.

Struc: 15 a.a.

Enzyme reactions

• Enzyme class: Chains C, D: E.C.2.3.1.48 - histone acetyltransferase.
• Reaction: L-lysyl-[protein] + acetyl-CoA = N₆-acetyl-L-lysyl-[protein] + CoA + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acs.jmedchem.6b00176

J Med Chem 59:3489-3498 (2016)

PubMed id: 27011007

Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's Disease.

S.J.Stachel, C.Zerbinatti, M.T.Rudd, M.Cosden, S.Suon, K.K.Nanda, K.Wessner, J.DiMuzio, J.Maxwell, Z.Wu, J.M.Uslaner, M.S.Michener, P.Szczerba, E.Brnardic, V.Rada, Y.Kim, R.Meissner, P.Wuelfing, Y.Yuan, J.Ballard, M.Holahan, D.J.Klein, J.Lu, X.Fradera, G.Parthasarathy, V.N.Uebele, Z.Chen, Y.Li, J.Li, A.J.Cooke, D.J.Bennett, M.T.Bilodeau, J.Renger.

ABSTRACT

Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.