title: Molecular determinants of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) binding to transient receptor potential V1 (TRPV1) channels.
abstract: Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) has been recognized as an important activator of certain transient receptor potential (TRP) channels. More specifically, TRPV1 is a pain receptor activated by a wide range of stimuli. However, whether or not PI(4,5)P2 is a TRPV1 agonist remains open to debate. Utilizing a combined approach of mutagenesis and molecular modeling, we identified a PI(4,5)P2 binding site located between the TRP box and the S4-S5 linker. At this site, PI(4,5)P2 interacts with the amino acid residues Arg-575 and Arg-579 in the S4-S5 linker and with Lys-694 in the TRP box. We confirmed that PI(4,5)P2 behaves as a channel agonist and found that Arg-575, Arg-579, and Lys-694 mutations to alanine reduce PI(4,5)P2 binding affinity. Additionally, in silico mutations R575A, R579A, and K694A showed that the reduction in binding affinity results from the delocalization of PI(4,5)P2 in the binding pocket. Molecular dynamics simulations indicate that PI(4,5)P2 binding induces conformational rearrangements of the structure formed by S6 and the TRP domain, which cause an opening of the lower TRPV1 channel gate.
authors.affiliation: From the Center for Bioinformatics and Molecular Simulation, Universidad de Talca, 2 Norte 685, Talca-Chile.
authors.forename: Horacio
authors.initials: H
authors.lastname: Poblete
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Oyarzún
authors.affiliation: Escuela de Medicina, Universidad de Valparaíso, Hontaneda 2664, Valparaíso, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Olivero
authors.affiliation: Institute of Computational Comparative Medicine, Department of Anatomy and Physiology, Kansas State University, P-200 Mosier Hall, Manhattan, Kansas 66506-5802.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Comer
authors.affiliation: Doctorado Fisicoquímica Molecular, Universidad Andrés Bello, Ave, Republica 275, Santiago, Chile.
authors.forename: Matías
authors.initials: M
authors.lastname: Zuñiga
authors.affiliation: Doctorado en Biotecnología, Universidad Andrés Bello, Av. Republica 217, Santiago, Chile, and Center for Bioinformatics and Integrative Biology, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Av. República 239, Santiago, Chile.
authors.forename: Romina V
authors.initials: RV
authors.lastname: Sepulveda
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Báez-Nieto
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: González Leon
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile, Center for Bioinformatics and Integrative Biology, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Av. República 239, Santiago, Chile fernando.gonzalez@unab.cl.
authors.forename: Fernando
authors.initials: F
authors.lastname: González-Nilo
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile, ramon.latorre@uv.cl.
authors.forename: Ramón
authors.initials: R
authors.lastname: Latorre
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D020285:Cryoelectron Microscopy; D004594:Electrophysiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D050916:TRPV Cation Channels / Q000737:chemistry*
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D001120:Arginine; D008239:Lysine
keywords: Ion Channel; Molecular Docking; Molecular Dynamics; Multiscale Simulation; PI(4,5)P2; TRPV1; Transient Receptor Potential Channels (TRP Channels); electrophysiology