Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands

Lisa Asano; Ichiaki Ito; Naoyuki Kuwabara; Tsuyoshi Waku; Junn Yanagisawa; Hiroyuki Miyachi; Toshiyuki Shimizu

doi:10.1016/j.febslet.2013.02.028

Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands

Lisa Asano, Ichiaki Ito, Naoyuki Kuwabara, Tsuyoshi Waku, Junn Yanagisawa, Hiroyuki Miyachi, Toshiyuki Shimizu

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.

Original language	English (US)
Pages (from-to)	957-963
Number of pages	7
Journal	FEBS Letters
Volume	587
Issue number	7
DOIs	https://doi.org/10.1016/j.febslet.2013.02.028
State	Published - Apr 2 2013
Externally published	Yes

Keywords

Agonism
Crystal structure
Non-secosteroidal ligand
Vitamin D receptor

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

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10.1016/j.febslet.2013.02.028

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title = "Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands",

abstract = "Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.",

keywords = "Agonism, Crystal structure, Non-secosteroidal ligand, Vitamin D receptor",

author = "Lisa Asano and Ichiaki Ito and Naoyuki Kuwabara and Tsuyoshi Waku and Junn Yanagisawa and Hiroyuki Miyachi and Toshiyuki Shimizu",

note = "Funding Information: We thank the beamline staff at SPring-8 for their assistance with data collection. This work was supported by funding from Japanese Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid (N.K., J.Y., H.M., T.S.). This work was supported in part by the Targeted Proteins Research Program of the Japan Science and Technology Corporation (JST) and by the Japan Society for the Promotion of Science (JSPS) (T.W.). We all declare that none of the authors have a financial interest related to this work. ",

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doi = "10.1016/j.febslet.2013.02.028",

language = "English (US)",

volume = "587",

pages = "957--963",

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T1 - Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands

AU - Asano, Lisa

AU - Ito, Ichiaki

AU - Kuwabara, Naoyuki

AU - Waku, Tsuyoshi

AU - Yanagisawa, Junn

AU - Miyachi, Hiroyuki

AU - Shimizu, Toshiyuki

N1 - Funding Information: We thank the beamline staff at SPring-8 for their assistance with data collection. This work was supported by funding from Japanese Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid (N.K., J.Y., H.M., T.S.). This work was supported in part by the Targeted Proteins Research Program of the Japan Science and Technology Corporation (JST) and by the Japan Society for the Promotion of Science (JSPS) (T.W.). We all declare that none of the authors have a financial interest related to this work.

PY - 2013/4/2

Y1 - 2013/4/2

N2 - Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.

AB - Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.

KW - Agonism

KW - Crystal structure

KW - Non-secosteroidal ligand

KW - Vitamin D receptor

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Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands

Abstract

Keywords

ASJC Scopus subject areas

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