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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
Univ East Anglia, UK.
Univ East Anglia, UK.
Univ East Anglia, UK.
Univ East Anglia, UK;Univ Texas Med Branch, USA.ORCID iD: 0000-0002-0051-762X
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2020 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, no 44, p. 10024-10034Article in journal (Refereed) Published
Abstract [en]

Ligand-based NMR techniques to study protein-ligand interactions are potent tools in drug design. Saturation transfer difference (STD) NMR spectroscopy stands out as one of the most versatile techniques, allowing screening of fragments libraries and providing structural information on binding modes. Recently, it has been shown that a multi-frequency STD NMR approach, differential epitope mapping (DEEP)-STD NMR, can provide additional information on the orientation of small ligands within the binding pocket. Here, the approach is extended to a so-called DEEP-STD NMR fingerprinting technique to explore the binding subsites of cholera toxin subunit B (CTB). To that aim, the synthesis of a set of new ligands is presented, which have been subject to a thorough study of their interactions with CTB by weak affinity chromatography (WAC) and NMR spectroscopy. Remarkably, the combination of DEEP-STD NMR fingerprinting and Hamiltonian replica exchange molecular dynamics has proved to be an excellent approach to explore the geometry, flexibility, and ligand occupancy of multi-subsite binding pockets. In the particular case of CTB, it allowed the existence of a hitherto unknown binding subsite adjacent to the GM1 binding pocket to be revealed, paving the way to the design of novel leads for inhibition of this relevant toxin.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020. Vol. 26, no 44, p. 10024-10034
Keywords [en]
cholera toxin inhibitors, DEEP-STD NMR, ligand-based NMR spectroscopy, multi-subsite binding pockets, protein-ligand interactions
National Category
Biochemistry and Molecular Biology
Research subject
Chemistry, Biochemistry
Identifiers
URN: urn:nbn:se:lnu:diva-97718DOI: 10.1002/chem.202001723ISI: 000550508800001PubMedID: 32449563Scopus ID: 2-s2.0-85088115393OAI: oai:DiVA.org:lnu-97718DiVA, id: diva2:1461795
Available from: 2020-08-27 Created: 2020-08-27 Last updated: 2021-05-07Bibliographically approved

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Bergström, Maria

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