PMID- 9218465
OWN - NLM
STAT- MEDLINE
DCOM- 19970818
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 272
IP  - 29
DP  - 1997 Jul 18
TI  - Mutational analysis reveals that all-trans-retinoic acid, 9-cis-retinoic acid, 
      and antagonist interact with distinct binding determinants of RARalpha.
PG  - 18267-72
AB  - Retinoids exert their pleiotropic effects on cell differentiation and 
      proliferation through specific nuclear receptors, the retinoic acid receptors 
      (RARs) and retinoid X receptors (RXRs). Two biologically highly active natural 
      retinoids have been identified, all-trans-retinoic acid (t-RA) and 9-cis-retinoic 
      acid (9-cis-RA). The RXRs exclusively bind 9-cis-RA, whereas the RARs bind both 
      isomers of RA with comparable affinity. Recently published results suggest that 
      RARs have the same binding site for t-RA and 9-cis-RA but with different 
      determinants (1-3). Antagonist binding on RARalpha has been suggested to induce 
      distinct conformational changes in comparison with agonist binding. To elucidate 
      the region minimally required for efficient binding of agonist (t-RA and 
      9-cis-RA) and antagonist Ro 41-5253 to the RARalpha, we generated N- and 
      C-terminally truncated mutants of the receptor. Characterization of these 
      deletion mutant proteins using protease mapping and ligand binding experiments 
      revealed that different parts of the ligand-binding domain are necessary for 
      t-RA, 9-cis-RA, and antagonist binding. Three distinct regions of the 
      ligand-binding domain of the human retinoic acid receptor-alpha are required for 
      binding of t-RA (RARalpha187-402), 9-cis-RA (RARalpha188-409), and the antagonist 
      Ro 41-5253 (RARalpha226-414).
FAU - Keidel, S
AU  - Keidel S
AD  - Preclinical Research, Department of Infectious Diseases, F. Hoffmann-La Roche 
      Ltd., CH-4070 Basel, Switzerland.
FAU - Lamour, F P
AU  - Lamour FP
FAU - Apfel, C M
AU  - Apfel CM
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Benzoates)
RN  - 0 (Chromans)
RN  - 0 (DNA Primers)
RN  - 0 (Peptide Fragments)
RN  - 0 (RARA protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoids)
RN  - 144092-31-9 (Ro 41-5253)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Alitretinoin
MH  - Benzoates/*metabolism
MH  - Binding Sites
MH  - Chromans/*metabolism
MH  - DNA Mutational Analysis
MH  - DNA Primers
MH  - Humans
MH  - Kinetics
MH  - Mutagenesis, Insertional
MH  - Mutagenesis, Site-Directed
MH  - Peptide Fragments/chemistry/metabolism
MH  - Polymerase Chain Reaction
MH  - Receptors, Retinoic Acid/*chemistry/*metabolism
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Retinoic Acid Receptor alpha
MH  - Retinoids/metabolism
MH  - Sequence Deletion
MH  - Tretinoin/*metabolism
EDAT- 1997/07/18 00:00
MHDA- 1997/07/18 00:01
CRDT- 1997/07/18 00:00
PHST- 1997/07/18 00:00 [pubmed]
PHST- 1997/07/18 00:01 [medline]
PHST- 1997/07/18 00:00 [entrez]
AID - S0021-9258(18)39148-8 [pii]
AID - 10.1074/jbc.272.29.18267 [doi]
PST - ppublish
SO  - J Biol Chem. 1997 Jul 18;272(29):18267-72. doi: 10.1074/jbc.272.29.18267.