FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4367553334> ?p ?o ?g. }

• W4367553334 endingPage "PR01" @default.
• W4367553334 startingPage "PR01" @default.
• W4367553334 abstract "Abstract RAS mutations occur in approximately 20% of human cancers including the majority of pancreatic ductal adenocarcinoma (PDAC), half of colorectal cancers, and a third of all lung cancers. In cases of oncogenic activating RAS mutations, GTP hydrolysis is impaired, and the protein is preferentially held in the active GTP-bound state. When activated, RAS triggers multiple proliferative signaling cascades, including the MAPK/ERK and PI3K pathways, to induce cell growth, division, and differentiation. In solution, RAS exists in two interconverting GTP-bound conformational states, State 1 (inactive) and State 2 (active). State 2 is the active conformation since it binds to RAS Binding Domain (RBD) of effector proteins. Though the State 1 conformation is GTP-bound, it is unable to bind effectors and represents an inactive KRAS conformation. This State 1/State 2 equilibrium is closely coupled to the conformations (γ1 and γ2) exhibited by the γ-phosphate of GTP and its analogues. Solution-state 31P NMR spectroscopy captures and quantifies the γ1 and γ2 peaks representing State 1 and State 2 (Spoerner M et al., JBC 2010). We have initiated solution-state NMR investigation to determine the structural differences between wild-type (WT) and oncogenic mutant KRAS proteins (G12C, G12D, G12V, Q61L, and G13D) when bound to GTP and GppNHp. We quantified the State 1/State 2 equilibrium using 31P NMR. Our results show that GppNHp-bound KRAS proteins harboring oncogenic mutations differentially modulate the State 1/State 2 conformational equilibria resulting in remarkable divergence in conformational populations compared to WT protein; a notion for presence of mutation induced structural plasticity. Much work on the structural biology, biophysics and biochemistry of KRAS proteins is done when bound to the non-hydrolysable GTP analogue, GppNHp. Strikingly, our 31P NMR results show that GTP-bound KRAS elicits significant variations in State 1 and State 2 populations in comparison to GppNHp-bound proteins. These data suggest GppNHp binding induces a significant increase in the State 1 population; an observation that does not translate into GTP-bound KRAS. Our results provide additional insights into the differential binding affinities seen between WT/mutant KRAS and effector proteins (e.g., Hunter JC et al., Mol Cancer Res 2015) as well as interpretation for State 1 conformations in KRAS crystal structures when bound to mostly GppNHp and not GTP. We have also applied this 31P NMR approach to the evaluation of KRAS small molecule inhibitors that shift the population equilibrium to the State 1 (inactive) conformation in the protein-ligand complex. This demonstrates an intriguing therapeutic opportunity and novel mechanism of action that we are further exploring as part of our drug discovery pipeline. Citation Format: Alok K. Sharma, Marcin Dyba, Dominic Esposito, Bin Wang, Pedro J. Beltran, Eli Wallace, Dwight Nissley, Frank McCormick, Anna E. Maciag. Structural plasticity of KRAS oncogenic mutants – A case of misleading conclusions from GTP analogues [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR01." @default.
• W4367553334 created "2023-05-01" @default.
• W4367553334 creator A5000314948 @default.
• W4367553334 creator A5006480894 @default.
• W4367553334 creator A5015198096 @default.
• W4367553334 creator A5025400322 @default.
• W4367553334 creator A5033732336 @default.
• W4367553334 creator A5046377031 @default.
• W4367553334 creator A5070272853 @default.
• W4367553334 creator A5070319506 @default.
• W4367553334 creator A5082685256 @default.
• W4367553334 date "2023-05-01" @default.
• W4367553334 modified "2023-10-16" @default.
• W4367553334 title "Abstract PR01: Structural plasticity of KRAS oncogenic mutants – A case of misleading conclusions from GTP analogues" @default.
• W4367553334 doi "https://doi.org/10.1158/1557-3125.ras23-pr01" @default.
• W4367553334 hasPublicationYear "2023" @default.
• W4367553334 type Work @default.
• W4367553334 citedByCount "0" @default.
• W4367553334 crossrefType "journal-article" @default.
• W4367553334 hasAuthorship W4367553334A5000314948 @default.
• W4367553334 hasAuthorship W4367553334A5006480894 @default.
• W4367553334 hasAuthorship W4367553334A5015198096 @default.
• W4367553334 hasAuthorship W4367553334A5025400322 @default.
• W4367553334 hasAuthorship W4367553334A5033732336 @default.
• W4367553334 hasAuthorship W4367553334A5046377031 @default.
• W4367553334 hasAuthorship W4367553334A5070272853 @default.
• W4367553334 hasAuthorship W4367553334A5070319506 @default.
• W4367553334 hasAuthorship W4367553334A5082685256 @default.
• W4367553334 hasConcept C104317684 @default.
• W4367553334 hasConcept C118716 @default.
• W4367553334 hasConcept C143065580 @default.
• W4367553334 hasConcept C181199279 @default.
• W4367553334 hasConcept C185592680 @default.
• W4367553334 hasConcept C207332259 @default.
• W4367553334 hasConcept C2776638253 @default.
• W4367553334 hasConcept C2781187634 @default.
• W4367553334 hasConcept C501734568 @default.
• W4367553334 hasConcept C51785407 @default.
• W4367553334 hasConcept C55493867 @default.
• W4367553334 hasConcept C86803240 @default.
• W4367553334 hasConceptScore W4367553334C104317684 @default.
• W4367553334 hasConceptScore W4367553334C118716 @default.
• W4367553334 hasConceptScore W4367553334C143065580 @default.
• W4367553334 hasConceptScore W4367553334C181199279 @default.
• W4367553334 hasConceptScore W4367553334C185592680 @default.
• W4367553334 hasConceptScore W4367553334C207332259 @default.
• W4367553334 hasConceptScore W4367553334C2776638253 @default.
• W4367553334 hasConceptScore W4367553334C2781187634 @default.
• W4367553334 hasConceptScore W4367553334C501734568 @default.
• W4367553334 hasConceptScore W4367553334C51785407 @default.
• W4367553334 hasConceptScore W4367553334C55493867 @default.
• W4367553334 hasConceptScore W4367553334C86803240 @default.
• W4367553334 hasIssue "5_Supplement" @default.
• W4367553334 hasLocation W43675533341 @default.
• W4367553334 hasOpenAccess W4367553334 @default.
• W4367553334 hasPrimaryLocation W43675533341 @default.
• W4367553334 hasRelatedWork W1602598704 @default.
• W4367553334 hasRelatedWork W2912277053 @default.
• W4367553334 hasRelatedWork W2923679366 @default.
• W4367553334 hasRelatedWork W2966060449 @default.
• W4367553334 hasRelatedWork W3202865057 @default.
• W4367553334 hasRelatedWork W3213757879 @default.
• W4367553334 hasRelatedWork W415165752 @default.
• W4367553334 hasRelatedWork W4200205405 @default.
• W4367553334 hasRelatedWork W4297093890 @default.
• W4367553334 hasRelatedWork W4308550080 @default.
• W4367553334 hasVolume "21" @default.
• W4367553334 isParatext "false" @default.
• W4367553334 isRetracted "false" @default.
• W4367553334 workType "article" @default.