4IA2

Diastereotopic and Deuterium Effects in Gemini

Summary for 4IA2

• Entry DOI: 10.2210/pdb4ia2/pdb
• Related: 2HCD 3O1D 3O1E 4IA1 4IA3 4IA7
• Descriptor: Vitamin D3 receptor A, Nuclear receptor coactivator 2, 21-NOR-9,10-SECOCHOLESTA-5,7,10(19)-TRIENE-1,3,25-TRIOL, 20-(4-HYDROXY-4-METHYLPENTYL)-, (1A,3B,5Z,7E), ... (4 entities in total)
• Functional Keywords: vdr-agonist complex, alpha helical sandwich, transciption regulator, dna, rxr, phosphorylation, nucleus, transcription-transcription activator complex, transcription/transcription activator
• Biological source: Danio rerio (leopard danio,zebra danio,zebra fish); More
• Cellular location: Nucleus: Q9PTN2 Q15596
• Total number of polymer chains: 2
• Total formula weight: 35999.18

Authors

Maehr, H.,Rochel, N.,Suh, N.,Uskokovic, M. (deposition date: 2012-12-06, release date: 2013-04-24, Last modification date: 2024-02-28)

Primary citation

Maehr, H.,Rochel, N.,Lee, H.J.,Suh, N.,Uskokovic, M.R.
Diastereotopic and deuterium effects in gemini.
J.Med.Chem., 56:3878-3888, 2013

PubMed Abstract: Changing the geminal methyl groups on 1α,25-dihydroxyvitamin D3 and its analogues to the deuterio versions generally improves the bioactivity. Derivatives of 1α,25-dihydroxyvitamin D3 with two chains emanating at C20, commonly referred to as gemini, are subject to the same phenomenon. Additionally, gemini with different side chains are susceptible to bioactivity differentials where the C17-C20 threo configuration usually imparts higher activity than the corresponding erythro arrangement. In an effort to analyze the deuterium effect on gemini with minimal diastereotopic distortion, we synthesized gemini with equal side chains but introduced deuterium diastereospecifically on either chain. We solved the crystal structures of these compounds in the zebra fish zVDR ligand binding domain as complexes with NCoA-2 coactivator peptide and correlated the findings with growth inhibition in a breast cancer cell line.

PubMed: 23566225
DOI: 10.1021/jm400032t

Experimental method

X-RAY DIFFRACTION (2.95 Å)