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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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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
Project titleProject leaderProject codeProject type
Biološka važnost dipeptidil peptidaze III i njezin utjecaj na zdravlje čovjeka-DPP3BioReSanja Tomić; Hrvoje BrkićIP-2018-01-2936HRZZ
Projekt razvoja karijera mladih istraživača – izobrazba novih doktora znanostiPetar OzretićDOK-2021-02-5821HRZZ
Depositing User: Petar Ozretić
Date Deposited: 08 Feb 2024 09:18
DOI: 10.3390/app14020562

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