1xap
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The crystal structure of the ligand-binding domain of RARbeta, a suspect | + | The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we demonstrate how to generate an RARbeta antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARbeta-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARbeta in vitro and in animal models. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Daris, J | + | [[Category: Daris, J P.]] |
[[Category: Germain, P.]] | [[Category: Germain, P.]] | ||
[[Category: Gronemeyer, H.]] | [[Category: Gronemeyer, H.]] | ||
[[Category: Kammerer, S.]] | [[Category: Kammerer, S.]] | ||
[[Category: Lapointe, P.]] | [[Category: Lapointe, P.]] | ||
| - | [[Category: Lera, A | + | [[Category: Lera, A R.De.]] |
[[Category: Marinier, A.]] | [[Category: Marinier, A.]] | ||
[[Category: Peluso-Iltis, C.]] | [[Category: Peluso-Iltis, C.]] | ||
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[[Category: Starrett, J.]] | [[Category: Starrett, J.]] | ||
[[Category: Tortolani, D.]] | [[Category: Tortolani, D.]] | ||
| - | [[Category: Zusi, F | + | [[Category: Zusi, F C.]] |
[[Category: TTB]] | [[Category: TTB]] | ||
[[Category: ligand binding domain]] | [[Category: ligand binding domain]] | ||
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[[Category: ttnpb]] | [[Category: ttnpb]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:53:01 2008'' |
Revision as of 13:53, 21 February 2008
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Structure of the ligand binding domain of the Retinoic Acid Receptor beta
Contents |
Overview
The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we demonstrate how to generate an RARbeta antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARbeta-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARbeta in vitro and in animal models.
Disease
Known disease associated with this structure: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome OMIM:[604283]
About this Structure
1XAP is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Rational design of RAR-selective ligands revealed by RARbeta crystal stucture., Germain P, Kammerer S, Perez E, Peluso-Iltis C, Tortolani D, Zusi FC, Starrett J, Lapointe P, Daris JP, Marinier A, de Lera AR, Rochel N, Gronemeyer H, EMBO Rep. 2004 Sep;5(9):877-82. PMID:15319780
Page seeded by OCA on Thu Feb 21 15:53:01 2008
Categories: Homo sapiens | Single protein | Daris, J P. | Germain, P. | Gronemeyer, H. | Kammerer, S. | Lapointe, P. | Lera, A R.De. | Marinier, A. | Peluso-Iltis, C. | Rochel, N. | Starrett, J. | Tortolani, D. | Zusi, F C. | TTB | Ligand binding domain | Nuclear receptor | Retinoic acid receptor beta | Ttnpb
