7RS8

Crystal Structure of the ER-alpha Ligand-binding Domain (L372S, L536S) in complex with DMERI-16

Summary for 7RS8

• Entry DOI: 10.2210/pdb7rs8/pdb
• Descriptor: Estrogen receptor, (1R,2S,4R)-5-(4-hydroxyphenyl)-N-(4-methoxyphenyl)-6-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-N-(2,2,2-trifluoroethyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide, ... (4 entities in total)
• Functional Keywords: er-alpha, ligand complex, dmeri, transcription, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 120099.94

Authors

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. (deposition date: 2021-08-11, release date: 2021-09-22, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.64 Å)