Rational design of RAR‐selective ligands revealed by RARβ crystal stucture
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- Pierre Germain
- Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP BP 10142, 67404 Illkirch Cedex CU de Strasbourg France
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- Sabrina Kammerer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP BP 10142, 67404 Illkirch Cedex CU de Strasbourg France
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- Efrén Pérez
- Universidade de Vigo, Facultade de Química 36200 Vigo Spain
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- Carole Peluso‐Iltis
- Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP BP 10142, 67404 Illkirch Cedex CU de Strasbourg France
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- David Tortolani
- Bristol‐Myers Squibb, Pharmaceutical Research Institute Princeton New Jersey 08543‐4000 USA
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- F Christopher Zusi
- Bristol‐Myers Squibb, 5 Research Parkway Wallingford Connecticut 06492 USA
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- John Starrett
- Bristol‐Myers Squibb, 5 Research Parkway Wallingford Connecticut 06492 USA
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- Philippe Lapointe
- Bristol‐Myers Squibb, 100 Boul de L'Industrie Candiac Quebec Canada
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- Jean‐Paul Daris
- Bristol‐Myers Squibb, 100 Boul de L'Industrie Candiac Quebec Canada
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- Anne Marinier
- Bristol‐Myers Squibb, 100 Boul de L'Industrie Candiac Quebec Canada
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- Angel R de Lera
- Universidade de Vigo, Facultade de Química 36200 Vigo Spain
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- Natacha Rochel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP BP 10142, 67404 Illkirch Cedex CU de Strasbourg France
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- Hinrich Gronemeyer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP BP 10142, 67404 Illkirch Cedex CU de Strasbourg France
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説明
<jats:p>The crystal structure of the ligand‐binding domain of RARβ, 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 RARβ to bind more bulky agonists. Accordingly, we identified a ligand that shows RARβ selectivity with a 100‐fold higher affinity to RARβ than to α or γ 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 RARα, γ antagonist and an RARβ agonist. In addition, we demonstrate how to generate an RARβ antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARβ‐selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARβ <jats:italic>in vitro</jats:italic> and in animal models.</jats:p>
収録刊行物
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- EMBO reports
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EMBO reports 5 (9), 877-882, 2004-09
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