2021
Structural basis for ligand reception by anaplastic lymphoma kinase
Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature 2021, 600: 148-152. PMID: 34819665, PMCID: PMC8639777, DOI: 10.1038/s41586-021-04141-7.Peer-Reviewed Original Research
2017
How Nothing Boosts Affinity: Hydrophobic Ligand Binding to the Virtually Vacated S1′ Pocket of Thermolysin
Krimmer S, Cramer J, Schiebel J, Heine A, Klebe G. How Nothing Boosts Affinity: Hydrophobic Ligand Binding to the Virtually Vacated S1′ Pocket of Thermolysin. Journal Of The American Chemical Society 2017, 139: 10419-10431. PMID: 28696673, DOI: 10.1021/jacs.7b05028.Peer-Reviewed Original ResearchConceptsWater moleculesPresent water moleculesWeak-binding ligandsAliphatic side chainsSpecificity pocketIsothermal titration calorimetrySolvent moleculesHigh-resolution crystallographyActive siteHydrophobic ligand bindingCrystalline stateElectron density mapsSide chainsTitration calorimetryS1 pocketNoble gas atomsSubstituentsThermodynamic signaturesFree energyHydration stateMoleculesLigands
2016
Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad
Radeva N, Schiebel J, Wang X, Krimmer S, Fu K, Stieler M, Ehrmann F, Metz A, Rickmeyer T, Betz M, Winquist J, Park A, Huschmann F, Weiss M, Mueller U, Heine A, Klebe G. Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad. Journal Of Medicinal Chemistry 2016, 59: 9743-9759. PMID: 27726357, DOI: 10.1021/acs.jmedchem.6b01195.Peer-Reviewed Original ResearchMeSH KeywordsAspartic Acid ProteasesBiocatalysisCalorimetryCarboxylic AcidsCatalytic DomainCrystallography, X-RayHydrazinesModels, MolecularPyrazolesConceptsFunctional groupsAspartic protease endothiapepsinCatalytic dyadCarboxylic acid fragmentOxygen functional groupsNovel functional groupsActive site mappingSteric demandWater moleculesFragment-growing strategyCrystal structureSide chainsFragment libraryHigh-quality crystalsS1 pocketScreening cascadeAcid fragmentCrystallographySpecificity pocketRelated fragmentsWarheadExperimental Active-Site Mapping by Fragments: Hot Spots Remote from the Catalytic Center of Endothiapepsin
Radeva N, Krimmer S, Stieler M, Fu K, Wang X, Ehrmann F, Metz A, Huschmann F, Weiss M, Mueller U, Schiebel J, Heine A, Klebe G. Experimental Active-Site Mapping by Fragments: Hot Spots Remote from the Catalytic Center of Endothiapepsin. Journal Of Medicinal Chemistry 2016, 59: 7561-7575. PMID: 27463859, DOI: 10.1021/acs.jmedchem.6b00645.Peer-Reviewed Original ResearchSix Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits: A Case Study
Schiebel J, Radeva N, Krimmer S, Wang X, Stieler M, Ehrmann F, Fu K, Metz A, Huschmann F, Weiss M, Mueller U, Heine A, Klebe G. Six Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits: A Case Study. ACS Chemical Biology 2016, 11: 1693-1701. PMID: 27028906, DOI: 10.1021/acschembio.5b01034.Peer-Reviewed Original Research
2014
Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors
Krimmer S, Betz M, Heine A, Klebe G. Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors. ChemMedChem 2014, 9: 833-846. PMID: 24623396, DOI: 10.1002/cmdc.201400013.Peer-Reviewed Original ResearchConceptsWater moleculesFirst solvation layerThermodynamic binding profilesProtein-ligand binding processHigh-resolution crystal structuresIsothermal titration calorimetrySolvation patternsCorrelation of structureSolvation layerEntropy-driven bindingThermolysin inhibitorsCongeneric seriesSingle methyl groupCrystal structureWater arrangementSolvent-exposed surfaceTitration calorimetryBinding processMethyl groupS2 pocketSubstituentsComplex formationBinding propertiesLigand binding propertiesBiological systems