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Structural proteomics defines a sequential priming mechanism for the progesterone receptor (XL-MS)

ABSTRACT: The progesterone receptor (PR) is a steroid-responsive nuclear receptor with two isoforms: PR-A and PR-B. Disruption of PR-A:PR-B signaling is associated with breast cancer through interactions with oncogenic co-regulatory proteins (CoRs). However, molecular details of isoform-specific PR-CoR interactions remain poorly understood. Using structural mass spectrometry, we investigate the sequential binding mechanism of purified full-length PR and intact CoRs, steroid receptor coactivator 3 (SRC3) and p300, as complexes on target DNA. Our findings reveal selective CoR NR-box binding by PR and novel interaction surfaces between PR and CoRs during complex assembly, providing a structural basis for CoR sequential binding on PR. Antagonist-bound PR showed persistent CoR interactions, challenging the classical model of nuclear receptor activation and repression. Collectively, we offer a peptide-level perspective on the organization of the PR transcriptional complex and infer the mechanisms behind the interactions of these proteins, both in active and inactive conformations.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Matthew Mann

LAB HEAD: Patrick R.

PROVIDER: PXD056360 | Pride | 2025-04-07

REPOSITORIES: Pride

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			Action	DRS
	20250115_PRASRC3p300_RU486_APO_DMSO_TR1.raw	Raw
	20250115_PRASRC3p300_RU486_APO_DMSO_TR2.raw	Raw
	20250115_PRASRC3p300_RU486_APO_DMSO_TR3.raw	Raw
	20250115_PRASRC3p300_RU486_APO_DSSO_TR1.raw	Raw
	20250115_PRASRC3p300_RU486_APO_DSSO_TR2.raw	Raw

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