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

• Main Author: Guangyu Wang
• Format: Article
• Language: English
• Published: Elsevier 2021-12-01
• Series: Biochemistry and Biophysics Reports
• Subjects: Sequential cooperativity; Active site stereoselectivity; Dominant steady-state ligand binding; Recessive transient ligand binding; Lipid-ligand interaction; Hydrogen bonding network
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405580821002041

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.