PDBsum entry 1exa

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Gene regulation PDB id
Protein chain
236 a.a. *
Waters ×312
* Residue conservation analysis
PDB id:
Name: Gene regulation
Title: Enantiomer discrimination illustrated by crystal structures of the human retinoic acid receptor hrargamma ligand binding domain: the complex with the active r-enantiomer bms270394.
Structure: Retinoic acid receptor gamma-2. Chain: a. Fragment: ligand binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: nucleus. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.59Å     R-factor:   0.209     R-free:   0.250
Authors: B.P.Klaholz,A.Mitschler,M.Belema,C.Zusi,D.Moras,Structural Proteomics In Europe (Spine)
Key ref:
B.P.Klaholz et al. (2000). Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma. Proc Natl Acad Sci U S A, 97, 6322-6327. PubMed id: 10841540 DOI: 10.1073/pnas.97.12.6322
02-May-00     Release date:   09-Jun-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P13631  (RARG_HUMAN) -  Retinoic acid receptor gamma
454 a.a.
236 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   3 terms 
  Biochemical function     DNA binding     4 terms  


DOI no: 10.1073/pnas.97.12.6322 Proc Natl Acad Sci U S A 97:6322-6327 (2000)
PubMed id: 10841540  
Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma.
B.P.Klaholz, A.Mitschler, M.Belema, C.Zusi, D.Moras.
The human retinoic acid receptor (hRAR) is a member of the nuclear receptor superfamily that regulates the transcription of target genes in a ligand-dependent manner. The three hRAR isotypes are targets for retinoids that are used in the treatment of various diseases, including breast cancer and skin diseases. Drug efficiency and safety depend on the pharmacological activity of enantiomers, which can differ because of the chiral environment generated by the target. We report the crystal structures of the hRARgamma ligand-binding domain bound to two enantiomers, the active BMS270394 and the inactive BMS270395, solved at 1.6 A and 1.7 A resolution, respectively. The crystal structures reveal that in both enantiomers, the hydroxyl moiety attached to the chiral center forms a hydrogen bond to the Met-272 sulfur atom, thus imposing a conformation of BMS270395 that differs significantly from that observed for BMS270394 and other known retinoids. BMS270395 adopts an energetically unfavorable conformation, accounting for its inactivity; in contrast, the conformation of BMS270394 is close to an energy minimum. Our high-resolution data allow rationalization of enantiomer discrimination by the receptor and provide a model system for the pharmacological properties of enantiomeric pairs.
  Selected figure(s)  
Figure 1.
Fig. 1. Stereo representation of the ligand-binding pocket of the crystal structure of the hRAR LBD with the bound active enantiomer BMS270394 (shown in orange). The final model is depicted with the ligand fitted to the electron density map (colored in red) that has been calculated at the very beginning of the refinement in absence of the ligand. The [A]-weighted F[obs] F[calc] map (18) at 1.59-Å resolution is contoured at 3.2 . Distances in yellow indicate hydrogen bonds and salt bridges between ligand and residues, whereas van der Waals contacts are shown in blue. RAR selectivity of the ligand is achieved by its hydroxyl group, which forms a hydrogen bond with the sulfur of Met-272, corresponding to isoleucines in RAR and . H3, H5, H10, and H11 indicate helices, and L6/7 the loop between helix 6 and 7.
Figure 2.
Fig. 2. Structure of hRAR LBD bound to the inactive BMS270395 and its comparison with the BMS270394 complex (stereo representations) (A). The BMS270395 complex with the initial refinement-unbiased [A]-weighted F[obs] F[calc] map at 1.67 Å resolution contoured at 3.2 and colored in violet. The map clearly indicates two possible positions for the fluorine atom, corresponding to two different ligand conformations. The up and down orientations of the fluorine atom have occupancies of 40/60%, respectively (colored in green and red, pointing to Ile-275 and Ala-234, respectively) (B). Superposition of the hRAR LBD complexes of both enantiomers as obtained by a least-squares fit. The position of the hydroxyl group oxygen is strictly conserved to maintain the hydrogen bond to Met-272; BMS270395 therefore adopts a conformation different from that observed for BMS270394 (C). Detailed view of the part of the ligand pocket where the ligand exhibits unfavorable contacts. The color code for distances is that of Fig. 1. The fluorine atom exhibits close contacts for both the up and down orientation, whereas the salt bridge between the carboxylate group and Arg-278 is weaker compared with the BMS270394 complex.

Literature references that cite this PDB file's key reference

  PubMed id Reference
18179220 A.R.Moise, M.Domínguez, S.Alvarez, R.Alvarez, M.Schupp, A.G.Cristancho, P.D.Kiser, Lera, M.A.Lazar, and K.Palczewski (2008).
Stereospecificity of retinol saturase: absolute configuration, synthesis, and biological evaluation of dihydroretinoids.
  J Am Chem Soc, 130, 1154-1155.  
18612831 D.C.Thompson, R.A.Denny, R.Nilakantan, C.Humblet, D.Joseph-McCarthy, and E.Feyfant (2008).
CONFIRM: connecting fragments found in receptor molecules.
  J Comput Aided Mol Des, 22, 761-772.  
18703560 E.Galdones, and B.F.Hales (2008).
Retinoic acid receptor gamma-induced misregulation of chondrogenesis in the murine limb bud in vitro.
  Toxicol Sci, 106, 223-232.  
17906643 Lera, W.Bourguet, L.Altucci, and H.Gronemeyer (2007).
Design of selective nuclear receptor modulators: RAR and RXR as a case study.
  Nat Rev Drug Discov, 6, 811-820.  
17906642 L.Altucci, M.D.Leibowitz, K.M.Ogilvie, Lera, and H.Gronemeyer (2007).
RAR and RXR modulation in cancer and metabolic disease.
  Nat Rev Drug Discov, 6, 793-810.  
17489579 M.I.Dawson, Z.Xia, G.Liu, M.Ye, J.A.Fontana, L.Farhana, B.B.Patel, S.Arumugarajah, M.Bhuiyan, X.K.Zhang, Y.H.Han, W.B.Stallcup, J.Fukushi, T.Mustelin, L.Tautz, Y.Su, D.L.Harris, N.Waleh, P.D.Hobbs, L.Jong, W.R.Chao, L.J.Schiff, and B.P.Sani (2007).
An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity.
  J Med Chem, 50, 2622-2639.  
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
15319780 P.Germain, S.Kammerer, E.Pérez, C.Peluso-Iltis, D.Tortolani, F.C.Zusi, J.Starrett, P.Lapointe, J.P.Daris, A.Marinier, Lera, N.Rochel, and H.Gronemeyer (2004).
Rational design of RAR-selective ligands revealed by RARbeta crystal stucture.
  EMBO Rep, 5, 877-882.
PDB code: 1xap
15502323 S.Kammerer, P.Germain, R.Flaig, C.Peluso-Iltis, A.Mitschler, N.Rochel, H.Gronemeyer, and D.Moras (2004).
RARbeta ligand-binding domain bound to an SRC-1 co-activator peptide: purification, crystallization and preliminary X-ray diffraction analysis.
  Acta Crystallogr D Biol Crystallogr, 60, 2048-2050.  
12733718 M.T.Mizwicki, and A.W.Norman (2003).
Two key proteins of the vitamin D endocrine system come into crystal clear focus: comparison of the X-ray structures of the nuclear receptor for 1alpha,25(OH)2 vitamin D3, the plasma vitamin D binding protein, and their ligands.
  J Bone Miner Res, 18, 795-806.  
12220491 B.Klaholz, and D.Moras (2002).
C-H...O hydrogen bonds in the nuclear receptor RARgamma--a potential tool for drug selectivity.
  Structure, 10, 1197-1204.
PDB code: 1fd0
12547017 F.C.Zusi, M.V.Lorenzi, and V.Vivat-Hannah (2002).
Selective retinoids and rexinoids in cancer therapy and chemoprevention.
  Drug Discov Today, 7, 1165-1174.  
11340063 A.C.Steinmetz, J.P.Renaud, and D.Moras (2001).
Binding of ligands and activation of transcription by nuclear receptors.
  Annu Rev Biophys Biomol Struct, 30, 329-359.  
11344298 G.Tocchini-Valentini, N.Rochel, J.M.Wurtz, A.Mitschler, and D.Moras (2001).
Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands.
  Proc Natl Acad Sci U S A, 98, 5491-5496.
PDB codes: 1ie8 1ie9
11406102 S.Goto, K.Kogure, K.Abe, Y.Kimata, K.Kitahama, E.Yamashita, and H.Terada (2001).
Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin.
  Biochim Biophys Acta, 1512, 251-258.  
11607933 U.Egner, N.Heinrich, M.Ruff, M.Gangloff, A.Mueller-Fahrnow, and J.M.Wurtz (2001).
Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists.
  Med Res Rev, 21, 523-539.  
11050318 W.Bourguet, P.Germain, and H.Gronemeyer (2000).
Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications.
  Trends Pharmacol Sci, 21, 381-388.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.