5ZWE

Covalent bond formation between histidine of Vitamin D receptor (VDR) and a full agonist having a vinyl ketone group via conjugate addition reaction

Summary for 5ZWE

• Entry DOI: 10.2210/pdb5zwe/pdb
• Descriptor: Vitamin D3 receptor, 13-meric peptide from DRIP205 NR2 BOX peptide, (6R)-6-[(1R,3aS,4E,7aR)-7a-methyl-4-[2-[(3R,5R)-4-methylidene-3,5-bis(oxidanyl)cyclohexylidene]ethylidene]-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]hept-1-en-3-one, ... (4 entities in total)
• Functional Keywords: hormone covalent modifier transcription factor vitamind3 enone michael addition electrophile, transcription
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 32564.51

Authors

Yoshizawa, M.,Itoh, T.,Anami, Y.,Kato, A.,Yoshimoto, N.,Yamamoto, K. (deposition date: 2018-05-15, release date: 2018-07-18, Last modification date: 2018-08-08)

Primary citation

Yoshizawa, M.,Itoh, T.,Hori, T.,Kato, A.,Anami, Y.,Yoshimoto, N.,Yamamoto, K.
Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands
J. Med. Chem., 61:6339-6349, 2018

PubMed Abstract: We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.

PubMed: 29936834
DOI: 10.1021/acs.jmedchem.8b00774

Experimental method

X-RAY DIFFRACTION (2.72 Å)