5KCW

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

Replaces:  5BPR

Summary for 5KCW

• Entry DOI: 10.2210/pdb5kcw/pdb
• Related: 5KCC 5KCD 5KCF 5KCT 5KCU 5KD9
• Descriptor: Estrogen receptor, NCOA2, (1S,2R,4S)-5,6-bis(4-hydroxyphenyl)-N-phenyl-N-(2,2,2-trifluoroethyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide, ... (4 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, ligand binding, protein-ligand complex, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 63485.51

Authors

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. (deposition date: 2016-06-07, release date: 2016-11-16, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.905 Å)