MOLECULAR BASIS OF MC1R ACTIVATION: MUTATION-INDUCED ALTERATIONS IN STRUCTURAL DYNAMICS

Fernando Guimarães Cavatão; Éderson Sales Moreira Pinto; Mathias J. Krause; Clarice Sampaio Alho; Marcio Dorn

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Paper Title

MOLECULAR BASIS OF MC1R ACTIVATION: MUTATION-INDUCED ALTERATIONS IN STRUCTURAL DYNAMICS

Authors

Fernando Guimarães Cavatão
Éderson Sales Moreira Pinto
Mathias J. Krause
Clarice Sampaio Alho
Marcio Dorn

Modality

Poster

Subject area

Proteins and Proteomics

Publishing Date

21/11/2024

Country of Publishing

Brazil | Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeeting-2024/832684-molecular-basis-of-mc1r-activation--mutation-induced-alterations-in-structural-dynamics

ISBN

978-65-272-0843-3

Keywords

MC1R, GPCR, Molecular Dynamics Simulations, Membrane Protein, Protein Mutations, Structural Dynamics

Summary

The MC1R protein belongs to the class A family of G protein-coupled receptors (GPCRs). MC1R is a receptor in melanocytes that plays a role in melanin synthesis - a pigment that colors the skin, hair, and eyes. In addition to melanocytes, MC1R is also found in leukocytes and other cell types, which play a role in anti-inflammatory signaling. Mutations in this protein can impact hair color, skin tone, tanning ability, and increase the risk of skin cancer. The MC1R protein is activated by the alpha-melanocyte-stimulating hormone (alpha-MSH), a polypeptide. Previous studies have shown that mutations affect the interaction between MC1R and alpha-MSH. However, the mechanism behind this process needs to be better understood. Our study aims to shed light on this mechanism using molecular dynamics (MD) simulations to analyze the Asp84Glu and Asp294His variants. We simulated, in quintuplicate, both the wild-type (WT) protein and the mutants with and without the ligand using the GROMACS software. We selected the CHARMM36m force field, known for its improvements in the simulation of membrane-protein systems. Our results reveal the importance of the Ca2+ ion in the orthosteric site for stabilizing the ligand binding with the receptor. Furthermore, the mutations induce unique conformations during state transitions, hindering the switch between active and inactive states and decreasing cellular levels of cAMP. Interestingly, Asp294His showed increased ligand affinity but decreased protein activity, highlighting that tighter binding does not always lead to increased activation. Our study provides insights into the molecular mechanisms underlying the impact of MC1R mutations on protein activity.

Title of the Event: 20º Congresso Brasileiro de Bioinformática: X-Meeting 2024
City of the Event: Salvador
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

CAVATÃO, Fernando Guimarães et al.. MOLECULAR BASIS OF MC1R ACTIVATION: MUTATION-INDUCED ALTERATIONS IN STRUCTURAL DYNAMICS.. In: X-Meeting presentations. Anais...Salvador(BA) Hotel Deville Prime, 2024. Available in: https//www.even3.com.br/anais/xmeeting-2024/832684-MOLECULAR-BASIS-OF-MC1R-ACTIVATION--MUTATION-INDUCED-ALTERATIONS-IN-STRUCTURAL-DYNAMICS. Access in: 17/05/2025