2HAS

Crystal structure of VDR LBD in complex with 2alpha-(1-propoxy) calcitriol

Summary for 2HAS

• Entry DOI: 10.2210/pdb2has/pdb
• Related: 1DB1 2HAM 2HAR 2HB7 2HB8
• Descriptor: Vitamin D3 receptor, 2ALPHA-PROPOXY-1ALPHA,25-DIHYDROXYVITAMIN D3 (3 entities in total)
• Functional Keywords: alpha helical sandwich, gene regulation
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P11473
• Total number of polymer chains: 1
• Total formula weight: 30280.06

Authors

Hourai, S.,Rochel, N.,Moras, D. (deposition date: 2006-06-13, release date: 2006-08-29, Last modification date: 2023-10-25)

Primary citation

Hourai, S.,Fujishima, T.,Kittaka, A.,Suhara, Y.,Takayama, H.,Rochel, N.,Moras, D.
Probing a Water Channel near the A-Ring of Receptor-Bound 1alpha,25-Dihydroxyvitamin D3 with Selected 2alpha-Substituted Analogues
J.Med.Chem., 49:5199-5205, 2006

PubMed Abstract: The crystal structure of the vitamin D receptor (VDR) in complex with 1 alpha,25(OH)2D3 revealed the presence of several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2 alpha substituted analogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, all analogues affect the presence and/or the location of the above water molecules. The integrity of the channel interactions and specific C-2 alpha analogue directed additional interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.

PubMed: 16913708
DOI: 10.1021/jm0604070

Experimental method

X-RAY DIFFRACTION (1.96 Å)