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PDBsum entry 3fal

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protein ligands Protein-protein interface(s) links
Signaling protein PDB id
3fal
Jmol
Contents
Protein chains
196 a.a. *
238 a.a. *
Ligands
REA ×2
LO2 ×2
Waters ×16
* Residue conservation analysis
PDB id:
3fal
Name: Signaling protein
Title: Humanrxr alpha & mouse lxr alpha complexed with retenoic acid and gsk2186
Structure: Retinoic acid receptor rxr-alpha. Chain: a, c. Fragment: residues 225-462. Synonym: retinoid x receptor alpha, nuclear receptor subfamily 2 group b member 1. Engineered: yes. Oxysterols receptor lxr-alpha. Chain: b, d. Fragment: residues 200-445.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: rxra, nr2b1. Expressed in: escherichia coli. Expression_system_taxid: 562. Thr.Mlxra2-00-455. Mus musculus. Mouse.
Resolution:
2.36Å     R-factor:   0.222     R-free:   0.278
Authors: E.Y.Chao,J.A.Caravella,M.A.Watson,N.Campobasso,S.Ghisletti, A.N.Billin,C.Galardi,T.M.Willson,W.J.Zuercher,J.L.Collins
Key ref: E.Y.Chao et al. (2008). Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity. J Med Chem, 51, 5758-5765. PubMed id: 18800767 DOI: 10.1021/jm800612u
Date:
17-Nov-08     Release date:   14-Apr-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
196 a.a.
Protein chains
Pfam   ArchSchema ?
Q9Z0Y9  (NR1H3_MOUSE) -  Oxysterols receptor LXR-alpha
Seq:
Struc:
445 a.a.
238 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     5 terms  

 

 
DOI no: 10.1021/jm800612u J Med Chem 51:5758-5765 (2008)
PubMed id: 18800767  
 
 
Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.
E.Y.Chao, J.A.Caravella, M.A.Watson, N.Campobasso, S.Ghisletti, A.N.Billin, C.Galardi, P.Wang, B.A.Laffitte, M.A.Iannone, B.J.Goodwin, J.A.Nichols, D.J.Parks, E.Stewart, R.W.Wiethe, S.P.Williams, A.Smallwood, K.H.Pearce, C.K.Glass, T.M.Willson, W.J.Zuercher, J.L.Collins.
 
  ABSTRACT  
 
A cocrystal structure of T1317 (3) bound to hLXRbeta was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 ( 20) as a high-affinity LXRbeta ligand (IC 50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRbeta reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21458278 H.Aoyama, K.Sugita, M.Nakamura, A.Aoyama, M.T.Salim, M.Okamoto, M.Baba, and Y.Hashimoto (2011).
Fused heterocyclic amido compounds as anti-hepatitis C virus agents.
  Bioorg Med Chem, 19, 2675-2687.  
20199390 K.B.Marcu, M.Otero, E.Olivotto, R.M.Borzi, and M.B.Goldring (2010).
NF-kappaB signaling: multiple angles to target OA.
  Curr Drug Targets, 11, 599-613.  
20133709 N.Li, M.A.Rivéra-Bermúdez, M.Zhang, J.Tejada, S.S.Glasson, L.A.Collins-Racie, E.R.Lavallie, Y.Wang, K.C.Chang, S.Nagpal, E.A.Morris, C.R.Flannery, and Z.Yang (2010).
LXR modulation blocks prostaglandin E2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model.
  Proc Natl Acad Sci U S A, 107, 3734-3739.  
20159957 N.Venteclef, T.Jakobsson, A.Ehrlund, A.Damdimopoulos, L.Mikkonen, E.Ellis, L.M.Nilsson, P.Parini, O.A.Jänne, J.A.Gustafsson, K.R.Steffensen, and E.Treuter (2010).
GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response.
  Genes Dev, 24, 381-395.  
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