Proteomics

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HDX-MS Analysis of RORg:RORE:SRC3 Complexes

ABSTRACT: The retinoic acid receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor that both underpins metabolic and immune functions and provides vantage to manipulate those processes pharmacologically. Despite its importance, our understanding of the ligand-dependent activities of RORγ is far from complete and developing a detailed structural model for RORγ pharmacology could provide a path towards the development of safe and efficacious therapeutics targeting the receptor. Herein, we examine the ligand-dependent assembly of recombinant RORγ:coregulator complexes on cognate DNA response elements using structural proteomics and small angle x-ray scattering. These studies reveal that the RORγ DNA binding domain can bind multiple different sequences of DNA, and that coregulatory proteins may be able to ‘sense’ the ligand- and DNA-bound status of RORγ. Overall, the efforts described herein will illuminate important aspects of RORγ activity and drug development that could lead to more efficacious treatments targeting this important receptor.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Timothy Strutzenberg  

LAB HEAD: Patrick R. Griffin

PROVIDER: PXD025765 | Pride | 2021-11-03

REPOSITORIES: Pride

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Publications

Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement.

Strutzenberg Timothy S TS   Zhu Yingmin Y   Novick Scott J SJ   Garcia-Ordonez Ruben D RD   Doebelin Christelle C   He Yuanjun Y   Chang Mi Ra MR   Kamenecka Theodore M TM   Edwards Dean P DP   Griffin Patrick R PR  

Journal of molecular biology 20210920 22

The retinoic acid receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor of the nuclear receptor super family that underpins metabolic activity, immune function, and cancer progression. Despite being a valuable drug target in health and disease, our understanding of the ligand-dependent activities of RORγ is far from complete. Like most nuclear receptors, RORγ must recruit coregulatory protein to enact the RORγ target gene program. To date, a majority of structural  ...[more]

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