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Identification, characterization, and comparison of n-alkanols and anesthetics binding to the C1b subdomain of protein kinase cα: similar function with different binding sites.
- Source :
-
Journal of receptor and signal transduction research [J Recept Signal Transduct Res] 2020 Apr; Vol. 40 (2), pp. 109-116. Date of Electronic Publication: 2020 Feb 13. - Publication Year :
- 2020
-
Abstract
- Protein kinase C (PKC) is a family of lipid-activated enzymes involved in anesthetic preconditioning signaling pathways. Previously, n -alkanols and general anesthetics have been found to activate PKC by binding to the kinase C1B subdomain. In the present study, we attempt to ascertain the molecular mechanism and interaction mode of human PKCα C1B subdomain with a variety of exogenous n -alkanols and volatile general anesthetics as well as endogenous activator phorbol ester (PE) and co-activator diacylglycerol (DG). Systematic bioinformatics analysis identifies three spatially vicinal sites on the subdomain surface to potentially accommodate small-molecule ligands, where the site 1 is a narrow, amphipathic pocket, the site 2 is a wide, flat and hydrophobic pocket, and the site 3 is a rugged, polar pocket. Further interaction modeling reveals that site 1 is the cognate binding region of natural PE activator, which can moderately simulate the kinase activity in an independent manner. The short-chain n -alkanols are speculated to also bind at the site to competitively inhibit PE-induced kinase activation. The long-chain n -alkanols and co-activator DG are found to target site 2 in a nonspecific manner, while the volatile anesthetics prefer to interact with site 3 in a specific manner. Since the site 1 is composed of two protein loops that are also shared by sites 2 and 3, binding of n -alkanols, DG and anesthetics to sites 2 and 3 can trigger a conformational displacement on the two loops, which enlarges the pocket size and changes the pocket configuration of site 1 through an allosteric mechanism, consequently enhancing kinase activation by improving PE affinity to the site.
- Subjects :
- Anesthetics pharmacology
Binding Sites drug effects
Diglycerides chemistry
Diglycerides pharmacology
Humans
Ligands
Lipids chemistry
Phorbol Esters chemistry
Phorbol Esters pharmacology
Protein Binding drug effects
Protein Kinase C-alpha antagonists & inhibitors
Signal Transduction drug effects
Anesthetics chemistry
Anesthetics, General chemistry
Protein Kinase C-alpha chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1532-4281
- Volume :
- 40
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of receptor and signal transduction research
- Publication Type :
- Academic Journal
- Accession number :
- 32054382
- Full Text :
- https://doi.org/10.1080/10799893.2020.1726950