Inherent Dynamics of Head Domain Correlates with ATP-Recognition of P2X4 Receptors: Insights Gained from Molecular Simulations

摘要: P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) will promote the development new therapeutic agents for pain, inflammation, bladder dysfunction osteoporosis. Recent crystal structures zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at subunit interface zfP2X4 receptors, which is occupied by conspicuous cluster basic residues to recognize triphosphate moiety ATP. Using engineered affinity labeling molecular modeling, least three sites (S1, S2 S3) within ABP have been identified that able adenine ring ATP, implying existence distinct AR modes ABP. The open structure confirms one (named AR1), ATP buried into site S1 while interacts with clustered residues. Why architecture favors AR1 not other two still remains unexplored. Here, we examine potential role inherent dynamics head domain, domain formation, determinant receptors. In silico docking binding free energy calculation revealed comparable characters modes. Inherent especially downward motion preference rather than AR2 AR3. Along closing movement loop139–146 loop169–183, structural rearrangements K70, K72, R298 R143 enabled discriminate from Our observations suggest essential determining allowing evaluation strategies aimed developing specific blockers/allosteric modulators preventing associated both channel activation