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Structural proteomics defines a sequential priming mechanism for the progesterone receptor

Matthew D. Mann,Min Wang,J. Ferreon,Phoebe S. Tsoi,Michael P. Suess,Antrix Jain,A. Malovannaya,Roberto Vera Alvarez,B. Pascal,Raj Kumar,D. Edwards,Patrick R. Griffin

Published 2025 in Nature Communications

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 unique 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. In this work, 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. The molecular mechanism between each progesterone receptor (PR) isoform and oncogenic co-regulators SRC3 and p300 is poorly understood. Here, the authors report PR isoform-specific interactions with these co-regulators and antagonist-driven protein interactions, challenging the classical model of nuclear receptor activation.

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