G-protein-coupled receptors(GPCRs)are important drug targets,which are in general activated by ligands and deliver signal to cytosolic ***,some experiments already indicated that GPCRs also give rise to constitutive a...
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G-protein-coupled receptors(GPCRs)are important drug targets,which are in general activated by ligands and deliver signal to cytosolic ***,some experiments already indicated that GPCRs also give rise to constitutive activity through some mutations(viz.,CAM),independent on the ligands,which are usually associated with different kinds of ***,the mechanisms of CAM and their roles in interactions with the drug-ligands have been unclear on ***,we used microsecond time-scale molecular dynamics simulations to study the effect of an important F282L mutation onβ2AR in order to address the questions *** aid of the principle component analysis and the correlation analysis,our results revealed that F282L mutation could increase instability of the overall structure,dramatic fluctuation of NPxxY and extracellular loops,and decrease restraining of helices through weakening the interhelical H-bonding,which should contribute to the constitutive activity reported by the *** addition,we also utilized the protein structure network(PSN)method to explore the impact of F282L mutation on the structural communication pathways ofβ*** result indicates that the mutant exhibits less information flows with respect to the wildβ***,the mutation weakens the role of TM6 in taking part in the signal transmission but enhances the impact of *** addition,we also used virtual screening method to study the impact of the mutation on the interaction with the drug *** to the active state ofβ2AR,the mutant exhibits higher enrichment factor for the agonists than the inverse agonists,in contrast to the result of the inactive state ofβ2AR(PDB ID:2RH1),indicating that the F282L mutation advances the activation ofβ*** a whole,our observations provide valuable information for understanding the mechanism of the mutation-caused constitutive activity of GPCR and related drug-design.
Ras mediates cell proliferation,survival and *** in K-Ras4B are predominant at residues G12,G13 and *** though all impair GAP-assisted GTP→GDP hydrolysis,the mutation frequencies of K-Ras4B in human cancers *** we ai...
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Ras mediates cell proliferation,survival and *** in K-Ras4B are predominant at residues G12,G13 and *** though all impair GAP-assisted GTP→GDP hydrolysis,the mutation frequencies of K-Ras4B in human cancers *** we aim to figure out their mechanisms and differential *** total,we performed 6.4μs molecular dynamics simulations on the wild-type K-Ras4B(K-Ras4B-GTP/GDP)catalytic domain,the K-Ras4B-GTP-GAP complex,and the mutants(K-Ras4B-GTP/GDP,K-Ras4B-GTP/GDP,K-Ras4B-GTP/GDP)and their complexes with *** addition,we simulated'exchanged'nucleotide *** comprehensive simulations reveal that in solution K-Ras4B-GTP exists in two,active and inactive,*** mutations differentially elicit an inactive-to-active conformational transition in K-Ras4B-GTP;in K-Ras4B-GDP they expose the bound nucleotide which facilitates the GDP-to-GTP *** mechanisms may help elucidate the differential mutational statistics in K-Ras4B-driven *** nucleotide simulations reveal that the conformational transition is more accessible in the GTP-to-GDP than in the GDP-to-GTP ***,GAP not only donates its R789arginine finger,but stabilizes the catalytically-competent conformation and pre-organizes catalytic residue Q61;mutations disturb the R789/Q61 organization,impairing GAP-mediated GTP ***,our simulations help provide a mechanistic explanation of key mutational events in one of the most oncogenic proteins in cancer.
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