Matches in SemOpenAlex for { <https://semopenalex.org/work/W2072023400> ?p ?o ?g. }
Showing items 1 to 75 of
75
with 100 items per page.
- W2072023400 abstract "The intermediate-conductance KCa3.1 channel and the related small-conductance KCa2 channels constitute potential pharmacological targets for immunosuppression, fibroproliferative disorders, hypertension and various neurological diseases. However, there currently is no available crystal structure or molecular model of these medically relevant targets that could be used for structure-assisted drug design. We used the Kv1.2-Kv2.1 channel structure (pdb id: 2R9R) as a template to generate a homology model of the KCa3.1 channel transmembrane region with the Rosetta modeling method. Docking of small molecules that are known to block KCa3.1 channel currents using Rosetta Dock generated structural channel - drug complexes that can be validated using experimental approaches. The lowest energy confirmation of the KCa3.1 channel complex with TRAM-34 identified T250 and V275 as interaction sites, two residues which had been previously demonstrated to completely abolish triarylmethane sensitivity when mutated to the corresponding residues in KCa2.3 channel. The model further correctly identified the interaction of the benzothiazinone-type KCa3.1 channel blocker NS6180 with T250 and V275 in KCa3.1 channel and modeled binding of the negative KCa2 channel gating modulator NS8593 to a KCa3.1-T250S- V275A mutant channel, which is blocked more potently by NS8593 than the WT-KCa2.3 channel. For the dihydropyridine nifedipine, which blocks KCa3.1 channels with low micromolar activity, the Rosetta model suggested a receptor site located between the pore lining S5 and S6 segment in agreement with available experimental data showing that nifedipine does not interact with T250 in the selectivity filter. The Rosetta KCa2/3 channel models can be used to understand the molecular mechanism of action of KCa channel blockers and gating modulators and assist with drug design efforts. Supported by RO1 GM076063 (to H.W.) and UC Davis startup (to V.Y-Y.)." @default.
- W2072023400 created "2016-06-24" @default.
- W2072023400 creator A5026660883 @default.
- W2072023400 creator A5087293334 @default.
- W2072023400 date "2014-01-01" @default.
- W2072023400 modified "2023-09-26" @default.
- W2072023400 title "Structural Modeling of KCa3.1 Channel Interaction with Small Molecules" @default.
- W2072023400 doi "https://doi.org/10.1016/j.bpj.2013.11.3022" @default.
- W2072023400 hasPublicationYear "2014" @default.
- W2072023400 type Work @default.
- W2072023400 sameAs 2072023400 @default.
- W2072023400 citedByCount "0" @default.
- W2072023400 crossrefType "journal-article" @default.
- W2072023400 hasAuthorship W2072023400A5026660883 @default.
- W2072023400 hasAuthorship W2072023400A5087293334 @default.
- W2072023400 hasBestOaLocation W20720234001 @default.
- W2072023400 hasConcept C121332964 @default.
- W2072023400 hasConcept C121932024 @default.
- W2072023400 hasConcept C12554922 @default.
- W2072023400 hasConcept C159110408 @default.
- W2072023400 hasConcept C169627665 @default.
- W2072023400 hasConcept C170493617 @default.
- W2072023400 hasConcept C181199279 @default.
- W2072023400 hasConcept C185592680 @default.
- W2072023400 hasConcept C194544171 @default.
- W2072023400 hasConcept C26873012 @default.
- W2072023400 hasConcept C41685203 @default.
- W2072023400 hasConcept C50254741 @default.
- W2072023400 hasConcept C55493867 @default.
- W2072023400 hasConcept C71924100 @default.
- W2072023400 hasConcept C83743174 @default.
- W2072023400 hasConcept C86803240 @default.
- W2072023400 hasConceptScore W2072023400C121332964 @default.
- W2072023400 hasConceptScore W2072023400C121932024 @default.
- W2072023400 hasConceptScore W2072023400C12554922 @default.
- W2072023400 hasConceptScore W2072023400C159110408 @default.
- W2072023400 hasConceptScore W2072023400C169627665 @default.
- W2072023400 hasConceptScore W2072023400C170493617 @default.
- W2072023400 hasConceptScore W2072023400C181199279 @default.
- W2072023400 hasConceptScore W2072023400C185592680 @default.
- W2072023400 hasConceptScore W2072023400C194544171 @default.
- W2072023400 hasConceptScore W2072023400C26873012 @default.
- W2072023400 hasConceptScore W2072023400C41685203 @default.
- W2072023400 hasConceptScore W2072023400C50254741 @default.
- W2072023400 hasConceptScore W2072023400C55493867 @default.
- W2072023400 hasConceptScore W2072023400C71924100 @default.
- W2072023400 hasConceptScore W2072023400C83743174 @default.
- W2072023400 hasConceptScore W2072023400C86803240 @default.
- W2072023400 hasLocation W20720234001 @default.
- W2072023400 hasOpenAccess W2072023400 @default.
- W2072023400 hasPrimaryLocation W20720234001 @default.
- W2072023400 hasRelatedWork W1968583465 @default.
- W2072023400 hasRelatedWork W1980859010 @default.
- W2072023400 hasRelatedWork W1982189990 @default.
- W2072023400 hasRelatedWork W2001908368 @default.
- W2072023400 hasRelatedWork W2006147674 @default.
- W2072023400 hasRelatedWork W2011870923 @default.
- W2072023400 hasRelatedWork W2030643759 @default.
- W2072023400 hasRelatedWork W2045375507 @default.
- W2072023400 hasRelatedWork W2056819560 @default.
- W2072023400 hasRelatedWork W2077857264 @default.
- W2072023400 hasRelatedWork W2153091138 @default.
- W2072023400 hasRelatedWork W2154001744 @default.
- W2072023400 hasRelatedWork W2158980611 @default.
- W2072023400 hasRelatedWork W2160388422 @default.
- W2072023400 hasRelatedWork W2327667929 @default.
- W2072023400 hasRelatedWork W2337701107 @default.
- W2072023400 hasRelatedWork W2515060678 @default.
- W2072023400 hasRelatedWork W2739992541 @default.
- W2072023400 hasRelatedWork W2810530720 @default.
- W2072023400 hasRelatedWork W3196386367 @default.
- W2072023400 isParatext "false" @default.
- W2072023400 isRetracted "false" @default.
- W2072023400 magId "2072023400" @default.
- W2072023400 workType "article" @default.