7RS1

Crystal Structure of the ER-alpha Ligand-binding Domain (L372S, L536S) in complex with DMERI-21

7RS1 の概要

• エントリーDOI: 10.2210/pdb7rs1/pdb
• 分子名称: Estrogen receptor, methyl 3-(4-{[(1S,2R,4S)-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonyl](2,2,2-trifluoroethyl)amino}phenyl)prop-2-enoate (3 entities in total)
• 機能のキーワード: er-alpha, ligand complex, dmeri, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 119928.44

構造登録者

Min, J.,Nwachukwu, J.C.,Min, C.K.,Njeri, J.W.,Srinivasan, S.,Rangarajan, E.S.,Nettles, C.C.,Yan, S.,Houtman, R.,Griffin, P.R.,Izard, T.,Katzenellenbogen, B.S.,Katzenellenbogen, J.A.,Nettles, K.W. (登録日: 2021-08-10, 公開日: 2021-09-08, 最終更新日: 2023-10-18)

主引用文献

Min, J.,Nwachukwu, J.C.,Min, C.K.,Njeri, J.W.,Srinivasan, S.,Rangarajan, E.S.,Nettles, C.C.,Sanabria Guillen, V.,Ziegler, Y.,Yan, S.,Carlson, K.E.,Hou, Y.,Kim, S.H.,Novick, S.,Pascal, B.D.,Houtman, R.,Griffin, P.R.,Izard, T.,Katzenellenbogen, B.S.,Katzenellenbogen, J.A.,Nettles, K.W.
Dual-mechanism estrogen receptor inhibitors.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Efforts to improve estrogen receptor-α (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.

PubMed: 34452998
DOI: 10.1073/pnas.2101657118

実験手法

X-RAY DIFFRACTION (1.59 Å)