Allosteric substrate release by a sialic acid TRAP transporter substrate binding protein.

Autor: Schneberger N; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Hendricks P; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Peter MF; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.; Biochemistry Center, Heidelberg University, Im Neuenheimer Feld 328, 69120, Heidelberg, Germany., Gehrke E; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Binder SC; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Koenig PA; Core Facility Nanobodies, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Menzel S; Core Facility Nanobodies, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Thomas GH; Department of Biology (Area 10), University of York, York, YO10 5YW, UK., Hagelueken G; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany. hagelueken@uni-bonn.de.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 Nov 23; Vol. 7 (1), pp. 1559. Date of Electronic Publication: 2024 Nov 23.
DOI: 10.1038/s42003-024-07263-6
Abstrakt: The tripartite ATP-independent periplasmic (TRAP) transporters enable Vibrio cholerae and Haemophilus influenzae to acquire sialic acid, aiding their colonization of human hosts. This process depends on SiaP, a substrate-binding protein (SBP) that captures and delivers sialic acid to the transporter. We identified 11 nanobodies that bind specifically to the SiaP proteins from H. influenzae (HiSiaP) and V. cholerae (VcSiaP). Two nanobodies inhibited sialic acid binding. Detailed structural and biophysical studies of one nanobody-SBP complex revealed an allosteric inhibition mechanism, preventing ligand binding and releasing pre-bound sialic acid. A hydrophobic surface pocket of the SBP is crucial for the allosteric mechanism and for the conformational rearrangement that occurs upon binding of sialic acid to the SBP. Our findings provide new clues regarding the mechanism of TRAP transporters, as well as potential starting points for novel drug design approaches to starve these human pathogens of important host-derived molecules.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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