7BHD

FimH in complex with alpha1,6 core-fucosylated oligomannose-3, crystallized in the trigonal space group

Summary for 7BHD

• Entry DOI: 10.2210/pdb7bhd/pdb
• Related: 2VCO
• Descriptor: Type 1 fimbrin D-mannose specific adhesin, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, NICKEL (II) ION, ... (5 entities in total)
• Functional Keywords: adhesin, fimh, core fucose, cell adhesion
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 2
• Total formula weight: 36449.22

Authors

Bridot, C.,Bouckaert, J.,Krammer, E.-M. (deposition date: 2021-01-11, release date: 2022-07-20, Last modification date: 2024-11-06)

Primary citation

Krammer, E.M.,Bridot, C.,Serna, S.,Echeverria, B.,Semwal, S.,Roubinet, B.,van Noort, K.,Wilbers, R.H.P.,Bourenkov, G.,de Ruyck, J.,Landemarre, L.,Reichardt, N.,Bouckaert, J.
Structural insights into a cooperative switch between one and two FimH bacterial adhesins binding pauci- and high-mannose type N-glycan receptors.
J.Biol.Chem., 299:104627-104627, 2023

PubMed Abstract: The FimH type-1 fimbrial adhesin allows pathogenic Escherichia coli to adhere to glycoproteins in the epithelial linings of human bladder and intestinal tract, by using multiple fimbriae simultaneously. Pauci- and high-mannose type N-glycans are natural FimH receptors on those glycoproteins. Oligomannose-3 and oligomannose-5 bind with the highest affinity to FimH by using the same Manα1,3Man branch. Oligomannose-6 is generated from oligomannose-5 in the next step of the biogenesis of high-mannose N-glycans, by the transfer of a mannose in α1,2-linkage onto this branch. Using serial crystallography and by measuring the kinetics of binding, we demonstrate that shielding the high-affinity epitope drives the binding of multiple FimH molecules. First, we profiled FimH glycan binding on a microarray containing paucimannosidic N-glycans and in a FimH LEctPROFILE assay. To make the transition to oligomannose-6, we measured the kinetics of FimH binding using paucimannosidic N-glycans, glycoproteins and all four α-dimannosides conjugated to bovine serum albumin. Equimolar mixed interfaces of the dimannosides present in oligomannose-6 and molecular dynamics simulations suggest a positive cooperativity in the bivalent binding of Manα1,3Manα1 and Manα1,6Manα1 dimannosides. The binding of core α1,6-fucosylated oligomannose-3 in cocrystals of FimH is monovalent but interestingly the GlcNAc1-Fuc moiety retains highly flexibility. In cocrystals with oligomannose-6, two FimH bacterial adhesins bind the Manα1,3Manα1 and Manα1,6Manα1 endings of the second trimannose core (A-4'-B). This cooperative switch towards bivalent binding appears sustainable beyond a molar excess of oligomannose-6. Our findings provide important novel structural insights for the design of multivalent FimH antagonists that bind with positive cooperativity.

PubMed: 36944399
DOI: 10.1016/j.jbc.2023.104627

Experimental method

X-RAY DIFFRACTION (1.4 Å)