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PDBsum entry 1fcz
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Gene regulation PDB id
1fcz

 

 

 

 

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Contents
Protein chain
235 a.a. *
Ligands
156
LMU
Waters ×305
* Residue conservation analysis
PDB id:
1fcz
Name: Gene regulation
Title: Isotype selectivity of the human retinoic acid nuclear receptor hrar: the complex with the panagonist retinoid bms181156
Structure: Retinoic acid receptor gamma-1. Chain: a. Fragment: ligand binding domain. Synonym: rar-gamma-1. Engineered: yes. Other_details: complexed with bms181156, residue 156
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.38Å     R-factor:   0.132     R-free:   0.174
Authors: B.P.Klaholz,A.Mitschler,D.Moras,Structural Proteomics In Europe (Spine)
Key ref:
B.P.Klaholz et al. (2000). Structural basis for isotype selectivity of the human retinoic acid nuclear receptor. J Mol Biol, 302, 155-170. PubMed id: 10964567 DOI: 10.1006/jmbi.2000.4032
Date:
19-Jul-00     Release date:   11-Sep-00    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P13631  (RARG_HUMAN) -  Retinoic acid receptor gamma from Homo sapiens
Seq:
Struc: 		454 a.a.
235 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1006/jmbi.2000.4032 J Mol Biol 302:155-170 (2000)
PubMed id: 10964567  
 
 
Structural basis for isotype selectivity of the human retinoic acid nuclear receptor.
B.P.Klaholz, A.Mitschler, D.Moras.
 
  ABSTRACT  
 
The human retinoic acid receptor (hRAR) belongs to the family of nuclear receptors that regulate transcription in a ligand-dependent way. The isotypes RARalpha,beta and gamma are distinct pharmacological targets for retinoids that are involved in the treatment of various skin diseases and cancers, in particular breast cancer and acute promyelocytic leukemia. Therefore, synthetic retinoids have been developed aiming at isotype selectivity and reduced side-effects. We report the crystal structures of three complexes of the hRARgamma ligand-binding domain (LBD) bound to agonist retinoids that possess selectivity either for RARgamma (BMS184394) or for RARbeta/gamma (CD564), or that are potent for all RAR-isotypes (panagonist BMS181156). The high resolution data (1.3-1. 5 A) provide a description at the atomic level of the ligand pocket revealing the molecular determinants for the different degrees of ligand selectivity. The comparison of the complexes of the chemically closely related retinoids BMS184394 and CD564 shows that the side-chain of Met272 adopts different conformations depending on the presence of a hydrogen bond between its sulfur atom and the ligand. This accounts for their different isotype selectivity. On the other hand, the difference between the pan- and the RARbeta, gamma-selective agonist is probably due to a steric discrimination at the level of the 2-naphthoic acid moiety of CD564. Based on this study, we propose a model for a complex with the RARgamma-specific agonist CD666 that shows the possible applications for structure-based drug design of RAR isotype-selective retinoids.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Detail of the W*-loop showing the non-planar peptide linkage between Ser215 and Ala216, and the double conformation of Ser215 that allows the formation of different hydrogen bonds for the stabilization of the W*-loop (stereo view). The s[A]-weighted 2 mF[o] -DF[c] electron density map (colored in blue) at 1.30 Å resolution is contoured at 1.5s. 		Figure 3.
Figure 3. The chemical similarity of the RARg-selective BMS184394 and the RARb,g-selective CD564 allows to attribute their different selectivity to their respective hydroxyl and keto groups (stereo views). (a) Final model of the BMS184394 complex depicted with the initial refinement-unbiased s[A]-weighted mF[o] -F[c] omit map (colored in violet) at 1.47 Å resolution contoured at 3.2s. The protein part is colored in green and the ligand in red. Although a racemic mixture has been used in co-crystallization only the R-enantiomer of BMS184394 is present exhibiting a hydrogen bond to the Met272 sulfur atom. (b) The CD564 complex with the ligand fitted to its electron density (s[A]-weighted mF[o] -F[c] omit map at 1.30 Å resolution contoured at 3.2s, colored in orange). The protein part is colored in blue and the ligand in orange. (c) The pocket superposition obtained by a least-squares fit of the BMS184394 and CD564 complexes illustrates that the conformation of the Met272 side-chain depends on the interaction pattern with the ligand. The movement of Met272 is mediated to Ile389 and Leu386. Note that Ile389 and Ser390 exhibit two independent conformations for each structure that are depicted in green and yellow for the BMS184394 complex and in blue and violet for the CD564 complex.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 302, 155-170) copyright 2000.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20536349 C.Schinke, S.Goel, T.D.Bhagat, L.Zhou, Y.Mo, R.Gallagher, G.W.Kabalka, L.C.Platanias, A.Verma, and B.Das (2010).
Design and synthesis of novel derivatives of all-trans retinoic acid demonstrate the combined importance of acid moiety and conjugated double bonds in its binding to PML-RAR-alpha oncogene in acute promyelocytic leukemia.
  Leuk Lymphoma, 51, 1108-1114.  
20340104 H.Muta, and N.Hirayama (2010).
Alpha sphere filter method: Application of pseudomolecular descriptors in virtual screening of 2D chemical structures.
  J Comput Chem, 31, 2225-2232.  
  19471584 C.Rochette-Egly, and P.Germain (2009).
Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs).
  Nucl Recept Signal, 7, e005.  
19582836 G.Wohlfahrt, J.Sipilä, and L.O.Pietilä (2009).
Field-based comparison of ligand and coactivator binding sites of nuclear receptors.
  Biopolymers, 91, 884-894.  
19653691 L.Salvi, J.G.Kim, and P.J.Walsh (2009).
Practical catalytic asymmetric synthesis of diaryl-, aryl heteroaryl-, and diheteroarylmethanols.
  J Am Chem Soc, 131, 12483-12493.  
17876816 B.Fischer, K.Fukuzawa, and W.Wenzel (2008).
Receptor-specific scoring functions derived from quantum chemical models improve affinity estimates for in-silico drug discovery.
  Proteins, 70, 1264-1273.  
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.  
18612514 D.L.Howard, and H.G.Kjaergaard (2008).
Hydrogen bonding to divalent sulfur.
  Phys Chem Chem Phys, 10, 4113-4118.  
18412341 M.C.Thielges, D.A.Case, and F.E.Romesberg (2008).
Carbon-deuterium bonds as probes of dihydrofolate reductase.
  J Am Chem Soc, 130, 6597-6603.  
17462987 A.L.Ambrosio, S.M.Dias, I.Polikarpov, R.B.Zurier, S.H.Burstein, and R.C.Garratt (2007).
Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma.
  J Biol Chem, 282, 18625-18633.
PDB code: 2om9
17906643 A.R.de 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, A.R.de Lera, and H.Gronemeyer (2007).
RAR and RXR modulation in cancer and metabolic disease.
  Nat Rev Drug Discov, 6, 793-810.  
17433757 S.Alvarez, P.Germain, R.Alvarez, F.Rodríguez-Barrios, H.Gronemeyer, and A.R.de Lera (2007).
Structure, function and modulation of retinoic acid receptor beta, a tumor suppressor.
  Int J Biochem Cell Biol, 39, 1406-1415.  
16170358 F.Piu, N.K.Gauthier, and F.Wang (2006).
Beta-arrestin 2 modulates the activity of nuclear receptor RAR beta2 through activation of ERK2 kinase.
  Oncogene, 25, 218-229.  
16839186 H.Escriva, S.Bertrand, P.Germain, M.Robinson-Rechavi, M.Umbhauer, J.Cartry, M.Duffraisse, L.Holland, H.Gronemeyer, and V.Laudet (2006).
Neofunctionalization in vertebrates: the example of retinoic acid receptors.
  PLoS Genet, 2, e102.  
16721894 J.G.Kim, and P.J.Walsh (2006).
From aryl bromides to enantioenriched benzylic alcohols in a single flask: Catalytic asymmetric arylation of aldehydes.
  Angew Chem Int Ed Engl, 45, 4175-4178.  
15955085 K.Foitzik, T.Spexard, M.Nakamura, U.Halsner, and R.Paus (2005).
Towards dissecting the pathogenesis of retinoid-induced hair loss: all-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-beta2 in the dermal papilla.
  J Invest Dermatol, 124, 1119-1126.  
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
15576033 E.S.Manas, Z.B.Xu, R.J.Unwalla, and W.S.Somers (2004).
Understanding the selectivity of genistein for human estrogen receptor-beta using X-ray crystallography and computational methods.
  Structure, 12, 2197-2207.
PDB codes: 1x7j 1x7r
15520817 H.Gronemeyer, J.A.Gustafsson, and V.Laudet (2004).
Principles for modulation of the nuclear receptor superfamily.
  Nat Rev Drug Discov, 3, 950-964.  
15319780 P.Germain, S.Kammerer, E.Pérez, C.Peluso-Iltis, D.Tortolani, F.C.Zusi, J.Starrett, P.Lapointe, J.P.Daris, A.Marinier, A.R.de 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.  
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.  
11860617 M.Schapira, R.Abagyan, and M.Totrov (2002).
Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine.
  BMC Struct Biol, 2, 1.  
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.  
11279800 D.J.Yang, A.Azhdarinia, P.Wu, D.F.Yu, W.Tansey, S.K.Kalimi, E.E.Kim, and D.A.Podoloff (2001).
In vivo and in vitro measurement of apoptosis in breast cancer cells using 99mTc-EC-annexin V.
  Cancer Biother Radiopharm, 16, 73-83.  
11710733 E.Garattini, and M.Terao (2001).
Cytodifferentiation: a novel approach to cancer treatment and prevention.
  Curr Opin Pharmacol, 1, 358-363.  
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
11389813 J.O.Boyle (2001).
Retinoid mechanisms and cyclins.
  Curr Oncol Rep, 3, 301-305.  
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.  
11350930 U.S.Singh, M.T.Kunar, Y.L.Kao, and K.M.Baker (2001).
Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase-2.
  EMBO J, 20, 2413-2423.  
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.

 

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