TY - JOUR
T1 - Molecular dynamics simulations depict structural motions of the whole human aryl hydrocarbon receptor influencing its binding of ligands and HSP90
AU - Rosales-Hernández, Martha Cecilia
AU - Bello, Martiniano
AU - Toledano, Jazziel Velazquez
AU - Feregrino, Barbara Citlali Escudero
AU - Correa Basurto, José
AU - Fragoso Morales, Leticia Guadalupe
AU - Torres-Ramos, Mónica Adriana
N1 - Publisher Copyright:
© 2023 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - The aryl hydrocarbon receptor (AhR) has broad biological functions when its ligands activate it; the non-binding interactions with AhR have not been fully elucidated due to the absence of a complete tridimensional (3D) structure. Therefore, utilization of the whole 3D structure from Homo sapiens AhR by in silico studies will allow us to better study and analyze the binding mode of its full and partial agonists, and antagonists, as well as its interaction with the HSP90 chaperone. The 3D AhR structure was obtained from I-TASSER and subjected to molecular dynamics (MD) simulations to obtain different structural conformations and determine the most populated AhR conformer by clustering analyses. The AhR-3D structures selected from MD simulations and those from clustering analyses were used to achieve docking studies with some of its ligands and protein–protein docking with HSP90. Once the AhR-3D structure was built, its Ramachandran maps and energy showed a well-qualified 3D model. MD simulations showed that the per-Arnt-Sim homology (PAS) PAS A, PAS B, and Q domains underwent conformational changes, identifying the conformation when agonists were binding also, and HSP90 was binding near the PAS A, PAS B, and Q domains. However, when antagonists are binding, HSP90 does not bind near the PAS A, PAS B, and Q domains. These studies show that the complex agonist-AhR-HSP90 can be formed, but this complex is not formed when an antagonist is binding. Knowing the conformations when the ligands bind to AHR and the behavior of HSP90 allows for an understanding of its activity. Communicated by Ramaswamy H. Sarma.
AB - The aryl hydrocarbon receptor (AhR) has broad biological functions when its ligands activate it; the non-binding interactions with AhR have not been fully elucidated due to the absence of a complete tridimensional (3D) structure. Therefore, utilization of the whole 3D structure from Homo sapiens AhR by in silico studies will allow us to better study and analyze the binding mode of its full and partial agonists, and antagonists, as well as its interaction with the HSP90 chaperone. The 3D AhR structure was obtained from I-TASSER and subjected to molecular dynamics (MD) simulations to obtain different structural conformations and determine the most populated AhR conformer by clustering analyses. The AhR-3D structures selected from MD simulations and those from clustering analyses were used to achieve docking studies with some of its ligands and protein–protein docking with HSP90. Once the AhR-3D structure was built, its Ramachandran maps and energy showed a well-qualified 3D model. MD simulations showed that the per-Arnt-Sim homology (PAS) PAS A, PAS B, and Q domains underwent conformational changes, identifying the conformation when agonists were binding also, and HSP90 was binding near the PAS A, PAS B, and Q domains. However, when antagonists are binding, HSP90 does not bind near the PAS A, PAS B, and Q domains. These studies show that the complex agonist-AhR-HSP90 can be formed, but this complex is not formed when an antagonist is binding. Knowing the conformations when the ligands bind to AHR and the behavior of HSP90 allows for an understanding of its activity. Communicated by Ramaswamy H. Sarma.
KW - AhR
KW - AhR agonist
KW - AhR antagonist
KW - docking
KW - molecular dynamics
UR - http://www.scopus.com/inward/record.url?scp=85147317128&partnerID=8YFLogxK
U2 - 10.1080/07391102.2023.2171132
DO - 10.1080/07391102.2023.2171132
M3 - Artículo
C2 - 36705144
AN - SCOPUS:85147317128
SN - 0739-1102
VL - 41
SP - 13138
EP - 13153
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 22
ER -