5KCD

Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with an N-methyl Substituted OBHS-N derivative

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5KCD の概要

• エントリーDOI: 10.2210/pdb5kcd/pdb
• 関連するPDBエントリー: 5KCC 5KCF 5KCT 5KCU 5KCW 5KD9
• 分子名称: Estrogen receptor, NCOA2, (1S,2R,4S)-5,6-bis(4-hydroxyphenyl)-N-methyl-N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide, ... (4 entities in total)
• 機能のキーワード: nuclear receptor, transcription factor, ligand binding, protein-ligand complex, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 62831.99

構造登録者

Nwachukwu, J.C.,Srinivasan, S.,Bruno, N.E.,Dharmarajan, V.,Goswami, D.,Kastrati, I.,Novick, S.,Nowak, J.,Zhou, H.B.,Boonmuen, N.,Zhao, Y.,Min, J.,Frasor, J.,Katzenellenbogen, B.S.,Griffin, P.R.,Katzenellenbogen, J.A.,Nettles, K.W. (登録日: 2016-06-06, 公開日: 2016-11-16, 最終更新日: 2024-03-06)

主引用文献

Srinivasan, S.,Nwachukwu, J.C.,Bruno, N.E.,Dharmarajan, V.,Goswami, D.,Kastrati, I.,Novick, S.,Nowak, J.,Cavett, V.,Zhou, H.B.,Boonmuen, N.,Zhao, Y.,Min, J.,Frasor, J.,Katzenellenbogen, B.S.,Griffin, P.R.,Katzenellenbogen, J.A.,Nettles, K.W.
Full antagonism of the estrogen receptor without a prototypical ligand side chain.
Nat. Chem. Biol., 13:111-118, 2017

PubMed Abstract: Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor, and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity.

PubMed: 27870835
DOI: 10.1038/nchembio.2236

実験手法

X-RAY DIFFRACTION (1.82 Å)