Structure-Based Design of Potent Small-Molecule Binders to the S-Component of the ECF Transporter for Thiamine

Energy‐coupling factor (ECF) transporters are membrane‐protein complexes that mediate vitamin uptake in prokaryotes. They bind the substrate through the action of a specific integral membrane subunit (S‐component) and power transport by hydrolysis of ATP in the three‐subunit ECF module. Here, we hav...

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Published in:	Chembiochem : a European journal of chemical biology Vol. 16; no. 5; pp. 819 - 826
Main Authors:	Swier, Lotteke J. Y. M., Monjas, Leticia, Guskov, Albert, de Voogd, Alrik R., Erkens, Guus B., Slotboom, Dirk J., Hirsch, Anna K. H.
Format:	Journal Article
Language:	English
Published:	Weinheim WILEY-VCH Verlag 23-03-2015 WILEY‐VCH Verlag Wiley Subscription Services, Inc
Subjects:	ATP-Binding Cassette Transporters - chemistry ATP-Binding Cassette Transporters - metabolism Bacterial Proteins - chemistry Bacterial Proteins - metabolism Binding sites Biological Transport Drug Design energy-coupling factor transporter Lactococcus lactis - chemistry membrane proteins Models, Molecular molecular recognition Molecular Structure Small Molecule Libraries - chemistry Small Molecule Libraries - metabolism structure-based design Thiamine - chemical synthesis Thiamine - chemistry Thiamine - metabolism Vitamin B X-ray diffraction energy-coupling factor transporter X-ray diffraction molecular recognition membrane proteins structure-based design
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Summary:	Energy‐coupling factor (ECF) transporters are membrane‐protein complexes that mediate vitamin uptake in prokaryotes. They bind the substrate through the action of a specific integral membrane subunit (S‐component) and power transport by hydrolysis of ATP in the three‐subunit ECF module. Here, we have studied the binding of thiamine derivatives to ThiT, a thiamine‐specific S‐component. We designed and synthesized derivatives of thiamine that bind to ThiT with high affinity; this allowed us to evaluate the contribution of the functional groups to the binding affinity. We determined six crystal structures of ThiT in complex with our derivatives. The structure of the substrate‐binding site in ThiT remains almost unchanged despite substantial differences in affinity. This work indicates that the structural organization of the binding site is robust and suggests that substrate release, which is required for transport, requires additional changes in conformation in ThiT that might be imposed by the ECF module. ThiT's tough: Thiamine derivatives capable of interacting with ThiT, the S‐component of the thiamine‐specific ECF transporter, have been designed and synthesized. The binding affinities and co‐crystal structures have been determined.
Bibliography:	European Research Council (ERC) - No. 282083 istex:2B96C246E27F32EAB43B4D00DD44D6A3902AFCC7 Ministry of Education, Culture and Science - No. 024.001.035 ArticleID:CBIC201402673 European Community's Seventh Framework Programme - No. N°283570 Netherlands Organisation for Scientific Research (NWO) - No. 728.011.104; No. 865.11.001 ark:/67375/WNG-KQ11JSJM-0 These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1439-4227 1439-7633
DOI:	10.1002/cbic.201402673