2ZMI

Crystal Structure of Rat Vitamin D Receptor Bound to Adamantyl Vitamin D Analogs: Structural Basis for Vitamin D Receptor Antagonism and/or Partial Agonism

Summary for 2ZMI

• Entry DOI: 10.2210/pdb2zmi/pdb
• Related: 2ZMH 2ZMJ
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (1R,3R,7E,17beta)-17-{(1S,2E,5R)-5-hydroxy-1-methyl-5-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]pent-2-en-1-yl}-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol, ... (6 entities in total)
• Functional Keywords: nuclear receptor-antagonist complex, dna-binding, metal-binding, nucleus, phosphoprotein, receptor, transcription, transcription regulation, zinc, zinc-finger, activator
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Nucleus: P13053; Nucleus (By similarity): A1L0Z0
• Total number of polymer chains: 2
• Total formula weight: 32794.81

Authors

Nakabayashi, M.,Yamada, S.,Tanaka, T.,Igarashi, M.,Yoshimoto, N.,Ikura, T.,Ito, N.,Makishima, M.,Tokiwa, H.,DeLuca, H.F.,Shimizu, M. (deposition date: 2008-04-19, release date: 2008-09-02, Last modification date: 2024-03-13)

Primary citation

Nakabayashi, M.,Yamada, S.,Yoshimoto, N.,Tanaka, T.,Igarashi, M.,Ikura, T.,Ito, N.,Makishima, M.,Tokiwa, H.,DeLuca, H.F.,Shimizu, M.
Crystal structures of rat vitamin d receptor bound to adamantyl vitamin d analogs: structural basis for vitamin d receptor antagonism and partial agonism
J.Med.Chem., 51:5320-5329, 2008

PubMed Abstract: The X-ray crystal structures of the rat VDR ligand-binding domain complexed with 19-norvitamin D compounds that contain an adamantyl substituent at the side-chain terminus, 2a (ADTT), 2b (ADNY), and 2c (ADMI4) and a coactivator peptide derived from DRIP205 are reported. These compounds show a series of partial agonistic (10-75% efficacy)/antagonistic activities. All of these complexed receptors are crystallized in the canonical active conformation, regardless of their activity profiles. The bulky adamantyl side chain does not crowd helix 12 but protrudes into the gap formed by helix 11, loop 11-12, helix 3, and loop 6-7, thereby widening the ligand binding pocket. We suggest that these structural changes destabilize the active protein conformation and reduce its contribution to equilibrium among the active and inactive conformations. The coactivator peptide traps the minor active conformation, and the equilibrium shifts to the active conformation. As a result, these ligands show partial agonistic activities.

PubMed: 18710208
DOI: 10.1021/jm8004477

Experimental method

X-RAY DIFFRACTION (1.7 Å)