TY - JOUR
T1 - Molecular dynamics simulations reveal initial structural and dynamic features for the A 2AR as a result of ligand binding
AU - Martínez-Archundia, Marlet
AU - Correa-Basurto, José
N1 - Funding Information:
The authors thank ICyTDF (PIRIVE09-9), CONACYT (132353 and 204908) and PIFI-SIP-COFAA/IPN for financial support. MMA thanks to CONACYT for postdoctoral fellowships.
PY - 2014
Y1 - 2014
N2 - G-protein-coupled receptors (GPCRs) are membrane proteins that have a wide variety of physiological roles. Adenosine receptors belong to the GPCR family. Adenosine receptors are implicated in many physiological disorders, such as Parkinson's disease, Huntington's disease, inflammatory and immune's disease and many others. Interestingly, crystal structures of the active and inactive conformations of the A2-subtype adenosine receptor (A2AR) have been solved. These two structures could be used to get insights about the conformational changes that occur during the process of activation/inactivation processes of this receptor. Therefore, two ligand-free simulations of the native active (PDB code: 3QAK) and inactive (PDB code: 3EML) conformations of the A2AR and two halo-simulations were carried out to observe the initial conformational changes induced by coupling adenosine to the inactive conformation and caffeine to the active conformation. Furthermore, we constructed an A2AR model that contained four thermostabilising mutations, L48A, T65A, Q89A and A54L, which had previously been determined to stabilise the bound conformation of the agonist, and we ran molecular dynamics simulations of this mutant to investigate how these point mutations might affect the inactive conformation of this receptor. This study provides insights about the initial structural and dynamic features that occur as a result of the binding of caffeine and adenosine in the active and inactive A2AR structures, respectively, as well as the introduction of some mutations on the inactive structure of the A2AR. Moreover, we provide useful and detailed information regarding structural features such as toggle switch and ionic lock during the activation/inactivation processes of this receptor.
AB - G-protein-coupled receptors (GPCRs) are membrane proteins that have a wide variety of physiological roles. Adenosine receptors belong to the GPCR family. Adenosine receptors are implicated in many physiological disorders, such as Parkinson's disease, Huntington's disease, inflammatory and immune's disease and many others. Interestingly, crystal structures of the active and inactive conformations of the A2-subtype adenosine receptor (A2AR) have been solved. These two structures could be used to get insights about the conformational changes that occur during the process of activation/inactivation processes of this receptor. Therefore, two ligand-free simulations of the native active (PDB code: 3QAK) and inactive (PDB code: 3EML) conformations of the A2AR and two halo-simulations were carried out to observe the initial conformational changes induced by coupling adenosine to the inactive conformation and caffeine to the active conformation. Furthermore, we constructed an A2AR model that contained four thermostabilising mutations, L48A, T65A, Q89A and A54L, which had previously been determined to stabilise the bound conformation of the agonist, and we ran molecular dynamics simulations of this mutant to investigate how these point mutations might affect the inactive conformation of this receptor. This study provides insights about the initial structural and dynamic features that occur as a result of the binding of caffeine and adenosine in the active and inactive A2AR structures, respectively, as well as the introduction of some mutations on the inactive structure of the A2AR. Moreover, we provide useful and detailed information regarding structural features such as toggle switch and ionic lock during the activation/inactivation processes of this receptor.
KW - adenosine
KW - caffeine
KW - conformational changes
KW - ionic lock
UR - http://www.scopus.com/inward/record.url?scp=84906783950&partnerID=8YFLogxK
U2 - 10.1080/08927022.2013.835485
DO - 10.1080/08927022.2013.835485
M3 - Artículo
SN - 0892-7022
VL - 40
SP - 996
EP - 1014
JO - Molecular Simulation
JF - Molecular Simulation
IS - 13
ER -