PDBsum entry 4znh

Transcription

PDB id: 4znh

Contents

Protein chains

239 a.a.

227 a.a.

Ligands

LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP ×2

OBC-OBC

OBC

Waters ×379

PDB id:

4znh

Name:

Transcription

Title:

Crystal structure of the er-alpha ligand-binding domain (y537s) in complex with a 2-fluoro-substituted obhs derivative

Structure:

Estrogen receptor. Chain: a, b. Fragment: ligand-binding domain, unp residues 301-559. Synonym: er,er-alpha,estradiol receptor,nuclear receptor subfamily 3 group a member 1. Engineered: yes. Mutation: yes. Nuclear receptor-interacting peptide. Chain: c, d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1, esr, nr3a1. Expressed in: escherichia coli. Expression_system_taxid: 469908. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.93Å R-factor: 0.205 R-free: 0.251

Authors:

J.C.Nwachukwu,S.Srinivasan,Y.Zheng,S.Wang,J.Min,C.Dong,Z.Liao, V.Cavett,J.Nowak,R.Houtman,K.E.Carlson,J.S.Josan,O.Elemento, J.A.Katzenellenbogen,H.B.Zhou,K.W.Nettles

Key ref:

J.C.Nwachukwu et al. (2016). Predictive features of ligand-specific signaling through the estrogen receptor. Mol Syst Biol, 12, 864. PubMed id: 27107013

Date:

04-May-15 Release date: 04-May-16

Protein chain

P03372  (ESR1_HUMAN) -  Estrogen receptor from Homo sapiens

Seq: 595 a.a.

Struc: 239 a.a.*

Protein chain

P03372  (ESR1_HUMAN) -  Estrogen receptor from Homo sapiens

Seq: 595 a.a.

Struc: 227 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Mol Syst Biol 12:864 (2016)

PubMed id: 27107013

Predictive features of ligand-specific signaling through the estrogen receptor.

J.C.Nwachukwu, S.Srinivasan, Y.Zheng, S.Wang, J.Min, C.Dong, Z.Liao, J.Nowak, N.J.Wright, R.Houtman, K.E.Carlson, J.S.Josan, O.Elemento, J.A.Katzenellenbogen, H.B.Zhou, K.W.Nettles.

ABSTRACT

Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERα.