1xap: Difference between revisions
No edit summary |
No edit summary |
||
| Line 4: | Line 4: | ||
|PDB= 1xap |SIZE=350|CAPTION= <scene name='initialview01'>1xap</scene>, resolution 2.1Å | |PDB= 1xap |SIZE=350|CAPTION= <scene name='initialview01'>1xap</scene>, resolution 2.1Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=TTB:4-[(1E)-2-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)PROP-1-ENYL]BENZOIC ACID'>TTB</scene> | |LIGAND= <scene name='pdbligand=TTB:4-[(1E)-2-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)PROP-1-ENYL]BENZOIC+ACID'>TTB</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1xap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xap OCA], [http://www.ebi.ac.uk/pdbsum/1xap PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1xap RCSB]</span> | |||
}} | }} | ||
| Line 14: | Line 17: | ||
==Overview== | ==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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
| Line 37: | Line 37: | ||
[[Category: Tortolani, D.]] | [[Category: Tortolani, D.]] | ||
[[Category: Zusi, F C.]] | [[Category: Zusi, F C.]] | ||
[[Category: ligand binding domain]] | [[Category: ligand binding domain]] | ||
[[Category: nuclear receptor]] | [[Category: nuclear receptor]] | ||
| Line 43: | Line 42: | ||
[[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 Mon Mar 31 00:47:06 2008'' | ||