2025
Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention
Bogin B, Levine Z. Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention. Journal Of Chemical Theory And Computation 2025, 21: 3204-3215. PMID: 40029731, DOI: 10.1021/acs.jctc.4c01160.Peer-Reviewed Original ResearchConceptsIslet amyloid polypeptideIntrinsically disordered proteinsConformational selectionDisordered proteinsHuman islet amyloid polypeptideMolecular dynamics simulationsStable binding sitesSelf-assembling sequencesIAPP sequenceFixed conformationAmyloid polypeptideUmbrella samplingBinding preferencesConformational specificityTwo-state modelDynamics simulationsConformational heterogeneityNew conformationsBinding sitesMolecular binding mechanismsConformationBinding mechanismFoldamersStructural conformationProtein
2024
Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells
Sevrin T, Imoto H, Robertson S, Rauch N, Dyn'ko U, Koubova K, Wynne K, Kolch W, Rukhlenko O, Kholodenko B. Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells. Cell Reports 2024, 43: 114710. PMID: 39240715, PMCID: PMC11474227, DOI: 10.1016/j.celrep.2024.114710.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaResistance to RAFResistant PDAC cellsPancreatic cancer cellsPancreatic ductal adenocarcinoma cell linesProtein expression profilesTumor-specific variationsIsogenic pairsCell-specific modelsConformational specificityERK signalingInhibitor combinationsERK pathwayKRAS mutationsTargeted therapyExpression profilesMEK inhibitorsDuctal adenocarcinomaCancer cellsKRAS mutantPhospho-ERKCell linesPDAC cellsCell viabilityDifferential sensitivity
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