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Lipid-dependent sequential allosteric activation of heat-sensing TRPV1 channels by anchor-stereoselective "hot" vanilloid compounds and analogs.

ABSTRACT: Both a silent resident phosphatidylinositol lipid and a "hot" vanilloid agonist capsaicin or resiniferatoxin have been shown to share the same inter-subunit binding pocket between a voltage sensor like domain and a pore domain in TRPV1. However, how the vanilloid competes off the resident lipid for allosteric TRPV1 activation is unknown. Here, the in sillico research suggested that anchor-stereoselective sequential cooperativity between an initial recessive transient silent weak ligand binding site and a subsequent dominant steady-state strong ligand binding site in the vanilloid pocket may facilitate the lipid release for allosteric activation of TRPV1 by vanilloids or analogs upon non-covalent interactions. Thus, the resident lipid may play a critical role in allosteric activation of TRPV1 by vanilloid compounds and analogs.

SUBMITTER: Wang G

PROVIDER: S-EPMC8416642 | biostudies-literature |

REPOSITORIES: biostudies-literature

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