7NFB
ER-PRS*(+) (Y537S) in complex with genistein and SRC-2 coactivator peptide
Summary for 7NFB
| Entry DOI | 10.2210/pdb7nfb/pdb |
| Related | 7NDO 7NEL |
| Descriptor | Estrogen receptor, Nuclear receptor coactivator 2, GENISTEIN, ... (8 entities in total) |
| Functional Keywords | human estrogen receptor alpha, hera-lbd, genistein, src-2, ligand binding domain, er, transcription |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 61947.54 |
| Authors | Kriegel, M.,Muller, Y.A. (deposition date: 2021-02-05, release date: 2021-08-25, Last modification date: 2024-01-31) |
| Primary citation | Kriegel, M.,Wiederanders, H.J.,Alkhashrom, S.,Eichler, J.,Muller, Y.A. A PROSS-designed extensively mutated estrogen receptor alpha variant displays enhanced thermal stability while retaining native allosteric regulation and structure. Sci Rep, 11:10509-10509, 2021 Cited by PubMed Abstract: Protein stability limitations often hamper the exploration of proteins as drug targets. Here, we show that the application of PROSS server algorithms to the ligand-binding domain of human estrogen receptor alpha (hERα) enabled the development of variant ER that comprises 24 amino acid substitutions and exhibits multiple improved characteristics. The protein displays enhanced production rates in E. coli, crystallizes readily and its thermal stability is increased significantly by 23 °C. hERα is a nuclear receptor (NR) family member. In NRs, protein function is allosterically regulated by its interplay with small molecule effectors and the interaction with coregulatory proteins. The in-depth characterization of ER shows that these cooperative effects are fully preserved despite that 10% of all residues were substituted Crystal structures reveal several salient features, i.e. the introduction of a tyrosine corner in a helix-loop-helix segment and the formation of a novel surface salt bridge network possibly explaining the enhanced thermal stability. ER shows that prior successes in computational approaches for stabilizing proteins can be extended to proteins with complex allosteric regulatory behaviors as present in NRs. Since NRs including hERα are implicated in multiple diseases, our ER variant shows significant promise for facilitating the development of novel hERα modulators. PubMed: 34006920DOI: 10.1038/s41598-021-89785-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.33 Å) |
Structure validation
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