2o4j: Difference between revisions
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==Overview== | ==Overview== | ||
We have successfully prepared E- and Z- isomers of 17-20 dehydro analogs | We have successfully prepared E- and Z- isomers of 17-20 dehydro analogs of 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD). Both isomers bind to the recombinant rat vitamin D receptor (VDR) with high affinity. The Z-isomer (Vit-III 17-20Z) displays activity in vivo and in vitro that is similar to 2MD. The in vitro activity of the E-isomer (Vit-III 17-20E) is comparable to the natural hormone, though in vivo this analog is significantly less calcemic. Crystal structures of the rat VDR ligand binding domain complexed with the analogs demonstrate that the Vit-III 17-20Z analog is oriented almost identically to 2MD, with only minor differences induced by the planar configuration around the C17-C20 double bond. The Vit-III 17-20E analog is oriented in a conformation distinct from both 2MD and the natural hormone. The structural comparisons suggest that the position of C21 in the ligand binding site may be an important determinant of biological activity. | ||
==Disease== | |||
Known diseases associated with this structure: Joubert syndrome 5 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610142 610142]], Leber congenital amaurosis, type X OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610142 610142]], Meckel syndrome type 4 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610142 610142]], Senior-Loken syndrome 6 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610142 610142]] | |||
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin | New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations., Vanhooke JL, Tadi BP, Benning MM, Plum LA, DeLuca HF, Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. Epub 2006 Dec 12. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17227670 17227670] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Benning, M | [[Category: Benning, M M.]] | ||
[[Category: DeLuca, H | [[Category: DeLuca, H F.]] | ||
[[Category: Vanhooke, J | [[Category: Vanhooke, J L.]] | ||
[[Category: VD4]] | [[Category: VD4]] | ||
[[Category: nuclear receptor-ligand complex]] | [[Category: nuclear receptor-ligand complex]] | ||
''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 18:14:22 2008'' | ||
Revision as of 19:14, 21 February 2008
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Crystal Structure of Rat Vitamin D Receptor Ligand Binding Domain Complexed with VitIII 17-20Z and the NR2 Box of DRIP 205
OverviewOverview
We have successfully prepared E- and Z- isomers of 17-20 dehydro analogs of 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD). Both isomers bind to the recombinant rat vitamin D receptor (VDR) with high affinity. The Z-isomer (Vit-III 17-20Z) displays activity in vivo and in vitro that is similar to 2MD. The in vitro activity of the E-isomer (Vit-III 17-20E) is comparable to the natural hormone, though in vivo this analog is significantly less calcemic. Crystal structures of the rat VDR ligand binding domain complexed with the analogs demonstrate that the Vit-III 17-20Z analog is oriented almost identically to 2MD, with only minor differences induced by the planar configuration around the C17-C20 double bond. The Vit-III 17-20E analog is oriented in a conformation distinct from both 2MD and the natural hormone. The structural comparisons suggest that the position of C21 in the ligand binding site may be an important determinant of biological activity.
DiseaseDisease
Known diseases associated with this structure: Joubert syndrome 5 OMIM:[610142], Leber congenital amaurosis, type X OMIM:[610142], Meckel syndrome type 4 OMIM:[610142], Senior-Loken syndrome 6 OMIM:[610142]
About this StructureAbout this Structure
2O4J is a Protein complex structure of sequences from Rattus norvegicus with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations., Vanhooke JL, Tadi BP, Benning MM, Plum LA, DeLuca HF, Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. Epub 2006 Dec 12. PMID:17227670
Page seeded by OCA on Thu Feb 21 18:14:22 2008