9gya

From Proteopedia

Vitamin D Receptor in complex with Sila-e

Structural highlights

9gya is a 2 chain structure with sequence from Danio rerio and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NCOA2_HUMAN Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.

Function

NCOA2_HUMAN Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.^[1]

Publication Abstract from PubMed

The incorporation of silicon bioisosteres into pharmacological structures has been used as a strategy to improve the therapeutic potential of drugs. However, no secosteroidal silicon-containing VDR ligands have been developed. Here we report the design, synthesis, and biological activity of six analogues of the natural hormone 1,25-dihydroxyvitamin D3 (1,25D(3)), which incorporate a silicon atom as a side chain-C25 isostere. The analogues were synthesized by the Wittig-Horner approach starting from Inhoffen-Lythgoe diol. The crystal structures of the complexes formed by the sila-analogues with the ligand binding domain of VDR revealed additional interactions of the sila-containing side chains that stabilize the VDR active conformation. These sila-analogues show similar VDR binding and transcriptional activity in comparison with the natural hormone 1,25D(3), but with significantly less hypercalcemic activity. The new analogues, when combined with chemotherapy, significantly decrease cell proliferation.

First Sila-Vitamin D Analogues: Design, Synthesis, Structural Analysis and Biological Activity.,Loureiro J, Seoane S, Sampaio-Dias IE, Peluso-Iltis C, Guiberteau T, Brito B, Gregorio C, Perez-Fernandez R, Rochel N, Mourino A, Rodriguez-Borges JE J Med Chem. 2024 Nov 29. doi: 10.1021/acs.jmedchem.4c02404. PMID:39610329^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998 Jan 15;17(2):507-19. PMID:9430642 doi:10.1093/emboj/17.2.507
↑ Loureiro J, Seoane S, Sampaio-Dias IE, Peluso-Iltis C, Guiberteau T, Brito B, Gregorio C, Pérez-Fernández R, Rochel N, Mouriño A, Rodríguez-Borges JE. First Sila-Vitamin D Analogues: Design, Synthesis, Structural Analysis and Biological Activity. J Med Chem. 2024 Nov 29. PMID:39610329 doi:10.1021/acs.jmedchem.4c02404