1. Mutation of Tyr137 of the universal Escherichia coli fimbrial adhesin FimH relaxes the tyrosine gate prior to mannose binding
- Author
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A Thompson, Sameh Eid, Julie Bouckaert, P. Zihlmann, Adam Zalewski, Martine Prévost, Said S. Rabbani, Goedele Roos, Eva-Maria Krammer, Beat Ernst, Marc F. Lensink, Roland R. Preston, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratory for the Structure and Function of Biological Membranes, Université libre de Bruxelles (ULB), CNRS, Université de Lille, University of Basel [Unibas], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Faculté de Médecine [Bruxelles] [ULB], Synchrotron SOLEIL [SSOLEIL], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université Libre de Bruxelles [Bruxelles] (ULB), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,biphenyl mannose ,tyrosine gate ,[SDV]Life Sciences [q-bio] ,Mutant ,Escherichia coli Infection ,Molecular dynamics ,medicine.disease_cause ,Biochemistry ,Pilus ,03 medical and health sciences ,thermodynamics ,Protein structure ,X-ray Crystallography ,medicine ,crystals ,FimH adhesin ,General Materials Science ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,protein structure ,Escherichia coli infection ,peptide torsions ,Escherichia coli ,ComputingMilieux_MISCELLANEOUS ,X-ray crystallography ,Crystallography ,biology ,Mannose binding ,Généralités ,General Chemistry ,heptyl mannose ,Thermodynamics ,molecular recognition ,Mutation ,Condensed Matter Physics ,Ligand (biochemistry) ,mutations ,molecular dynamics ,3. Good health ,Bacterial adhesin ,[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry ,030104 developmental biology ,QD901-999 ,Pilin ,biology.protein - Abstract
The most prevalent diseases manifested by Escherichia coli are acute and recurrent bladder infections and chronic inflammatory bowel diseases such as Crohn's disease. E. coli clinical isolates express the FimH adhesin, which consists of a mannose-specific lectin domain connected via a pilin domain to the tip of type 1 pili. Although the isolated FimH lectin domain has affinities in the nanomolar range for all high-mannosidic glycans, differentiation between these glycans is based on their capacity to form predominantly hydrophobic interactions within the tyrosine gate at the entrance to the binding pocket. In this study, novel crystal structures of tyrosine-gate mutants of FimH, ligand-free or in complex with heptyl α-d-O-mannopyranoside or 4-biphenyl α-d-O-mannopyranoside, are combined with quantum-mechanical calculations and molecular-dynamics simulations. In the Y48A FimH crystal structure, a large increase in the dynamics of the alkyl chain of heptyl α-d-O-mannopyranoside attempts to compensate for the absence of the aromatic ring; however, the highly energetic and stringent mannose-binding pocket of wild-type FimH is largely maintained. The Y137A mutation, on the other hand, is the most detrimental to FimH affinity and specificity: (i) in the absence of ligand the FimH C-terminal residue Thr158 intrudes into the mannose-binding pocket and (ii) ethylenediaminetetraacetic acid interacts strongly with Glu50, Thr53 and Asn136, in spite of multiple dialysis and purification steps. Upon mutation, pre-ligand-binding relaxation of the backbone dihedral angles at position 137 in the tyrosine gate and their coupling to Tyr48 via the interiorly located Ile52 form the basis of the loss of affinity of the FimH adhesin in the Y137A mutant., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2017