Let’s Talk about Sex Hormone Receptors and Their Physical Interaction with Sonic Hedgehog Protein: A Computational Study with Emphasis on Progesterone Receptor

Tomić, Antonija; Čonkaš, Josipa; Ozretić, Petar (2024) Let’s Talk about Sex Hormone Receptors and Their Physical Interaction with Sonic Hedgehog Protein: A Computational Study with Emphasis on Progesterone Receptor. Applied Sciences, 14 (2). p. 562. ISSN 2076-3417

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Abstract

The mature form of the sonic hedgehog protein (SHH-N) is the main canonical activator of the Hedgehog-GLI signaling pathway whose aberrant activity can lead to the development of hormone-dependent cancers like breast or prostate cancer. In this study, we employed computational methods to explore the potential binding of SHH-N with the progesterone receptor (PR), the sole member of the nuclear sex hormone receptor (SHRs) subfamily not previously linked to SHH-N. Through a combination of molecular docking, robust molecular dynamics (MD) simulations, and free energy calculations, we predicted a stable binding between SHH-N-cholesterol and PR. To validate our findings, we extended our in silico investigation to encompass the complexes between SHH-N-cholesterol and estrogen receptor alpha (ERα) and androgen receptor (AR)—complexes that have been experimentally confirmed in our prior studies. The calculations not only confirmed the stable binding of SHH-N-cholesterol with both ERα and AR but also revealed the strongest binding occurred with ERα, followed by AR and PR, suggesting a non-canonical interaction with potential biological significance. Microsecond-long MD simulations unveiled tight cholesterol binding in the SHRs’ binding sites, and we gained insights into sub-molecular interactions contributing to protein-protein stabilization in complexes involving PR and ERα for the first time. The MM/PBSA calculations indicated comparable binding affinities of PR for progesterone and SHH-N-cholesterol, with ERα exhibiting a more favorable enthalpy of binding with SHH-N-cholesterol than with estradiol.

Item Type:	Article
Uncontrolled Keywords:	sex hormone receptors; progesterone receptor; Hedgehog-GLI; sonic hedgehog; protein-protein docking; protein-protein interactions; molecular dynamic simulations
Subjects:	NATURAL SCIENCES > Chemistry > Theoretical Chemistry BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Human Genetics, Genomics and Proteomics
Divisions:	Division of Molecular Medicine Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Biološka važnost dipeptidil peptidaze III i njezin utjecaj na zdravlje čovjeka-DPP3BioRe Sanja Tomić; Hrvoje Brkić IP-2018-01-2936 HRZZ Projekt razvoja karijera mladih istraživača – izobrazba novih doktora znanosti Petar Ozretić DOK-2021-02-5821 HRZZ
Depositing User:	Dr.sc. Petar Ozretić
Date Deposited:	08 Feb 2024 09:18
URI:	http://fulir.irb.hr/id/eprint/8545
DOI:	10.3390/app14020562

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