Paper Citing NAMD - Abstract
Poblete, Horacio; Oyarzun, Ingrid; Olivero, Pablo; Comer, Jeffrey; Zuniga, Matias; Sepulveda, Ronnina V.; Baez-Nieto, David; Gonzalez Leon, Carlos; Gonzalez-Nilo, Fernando; Latorre, Ramon
Molecular Determinants of Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P-2) Binding to Transient Receptor Potential V1 (TRPV1) Channels
JOURNAL OF BIOLOGICAL CHEMISTRY, 290:2086-2098, JAN 23 2015
Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) 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)P-2 is a TRPV1 agonist remains open to debate. Utilizing a combined approach of mutagenesis and molecular modeling, we identified a PI(4,5)P-2 binding site located between the TRP box and the S4-S5 linker. At this site, PI(4,5)P-2 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)P-2 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)P-2 in the binding pocket. Molecular dynamics simulations indicate that PI(4,5)P-2 binding induces conformational rearrangements of the structure formed by S6 and the TRP domain, which cause an opening of the lower TRPV1 channel gate.
