Artículo
Exploring Multi-Subsite Binding Pockets in Proteins: DEEP-STD NMR Fingerprinting and Molecular Dynamics Unveil a Cryptic Subsite at the GM1 Binding Pocket of Cholera Toxin B
Autor/es | Monaco, Serena
Walpole, Samuel Doukani, Hassan Nepravishta, Ridvan Martínez Bailén, Macarena Carmona Asenjo, Ana Teresa Ramos Soriano, Francisco Javier Robina Ramírez, Inmaculada Angulo Álvarez, Jesús |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2020 |
Fecha de depósito | 2022-05-27 |
Publicado en |
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Resumen | Ligand-based NMRtechniquesto studyprotein–ligandinteractionsare potenttoolsin drugdesign.Satura-tiontransfer difference (STD)NMRspectroscopystandsoutas one of the mostversatiletechniques,allowing screeningof fragmentslibraries ... Ligand-based NMRtechniquesto studyprotein–ligandinteractionsare potenttoolsin drugdesign.Satura-tiontransfer difference (STD)NMRspectroscopystandsoutas one of the mostversatiletechniques,allowing screeningof fragmentslibraries andproviding structural informationon bindingmodes.Recently,ithas beenshown that amulti-frequencySTD NMRapproach, differential epitopemapping(DEEP)-STDNMR,can provideadditionalinformationon theorientationof smallligandswithinthe bindingpocket.Here,the approachis extendedtoaso-calledDEEP-STDNMRfin-gerprintingtechniqueto explorethe bindingsubsitesofcholeratoxinsubunitB(CTB).To thataim,the synthesis of aset of newligandsispresented, whichhavebeensubjecttoathoroughstudy of theirinteractionswithCTB by weakaf-finitychromatography(WAC)andNMRspectroscopy.Re-markably,the combination of DEEP-STDNMRfingerprintingandHamiltonianreplicaexchangemolecular dynamicshasprovedtobean excellent approachto explore the geome-try,flexibility,and ligandoccupancy of multi-subsitebindingpockets.Inthe particularcaseof CTB,it allowed the exis-tenceof ahitherto unknownbindingsubsiteadjacent to theGM1bindingpocketto be revealed, pavingthe wayto thedesignof novelleadsfor inhibition of this relevanttoxin. |
Agencias financiadoras | Ministerio de Economía y Competitividad (MINECO). España Junta de Andalucía Universidad de Sevilla |
Identificador del proyecto | CTQ2012-31247
CTQ2016-77270-R FQM-345 |
Cita | Monaco, S., Walpole, S., Doukani, H., Nepravishta, R., Martínez Bailén, M., Carmona Asenjo, A.T.,...,Angulo Álvarez, J. (2020). Exploring Multi-Subsite Binding Pockets in Proteins: DEEP-STD NMR Fingerprinting and Molecular Dynamics Unveil a Cryptic Subsite at the GM1 Binding Pocket of Cholera Toxin B. Chemistry-A European Journal, 26 (44), 10024-10034. |
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