6WMQ

Crystal Structure of Human REV-ERBbeta Ligand Binding Domain Co-Bound to Heme and NCoR ID1 Peptide

Summary for 6WMQ

• Entry DOI: 10.2210/pdb6wmq/pdb
• Descriptor: Nuclear receptor Rev-ErbA beta variant 1, Nuclear receptor corepressor 1, PROTOPORPHYRIN IX CONTAINING FE, ... (4 entities in total)
• Functional Keywords: nuclear receptor, heme-binding protein, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 51705.01

Authors

Mosure, S.A.,Shang, J.,Kojetin, D.J. (deposition date: 2020-04-21, release date: 2021-02-17, Last modification date: 2023-10-18)

Primary citation

Mosure, S.A.,Strutzenberg, T.S.,Shang, J.,Munoz-Tello, P.,Solt, L.A.,Griffin, P.R.,Kojetin, D.J.
Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERB beta.
Sci Adv, 7:-, 2021

PubMed Abstract: Heme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), but how heme regulates REV-ERB activity remains unclear. Cellular studies indicate that heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription. However, fluorescence-based biochemical assays suggest that heme displaces NCoR; here, we show that this is due to a heme-dependent artifact. Using ITC and NMR spectroscopy, we show that heme binding remodels the thermodynamic interaction profile of NCoR receptor interaction domain (RID) binding to REV-ERBβ ligand-binding domain (LBD). We solved two crystal structures of REV-ERBβ LBD cobound to heme and NCoR peptides, revealing the heme-dependent NCoR binding mode. ITC and chemical cross-linking mass spectrometry reveals a 2:1 LBD:RID stoichiometry, consistent with cellular studies showing that NCoR-dependent repression of REV-ERB transcription occurs on dimeric DNA response elements. Our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.

PubMed: 33571111
DOI: 10.1126/sciadv.abc6479

Experimental method

X-RAY DIFFRACTION (2.55 Å)