8by3

From Proteopedia

FimH lectin domain in complex with oligomannose-6

Structural highlights

8by3 is a 4 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.186Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FIMH_ECOLI Involved in regulation of length and mediation of adhesion of type 1 fimbriae (but not necessary for the production of fimbriae). Adhesin responsible for the binding to D-mannose. It is laterally positioned at intervals in the structure of the type 1 fimbriae. In order to integrate FimH in the fimbriae FimF and FimG are needed.

Publication Abstract from PubMed

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 Manalpha1,3Man 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 alpha1,2-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 alpha-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 Manalpha1,3Manalpha1 and Manalpha1,6Manalpha1 dimannosides. The binding of core alpha1,6-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 Manalpha1,3Manalpha1 and Manalpha1,6Manalpha1 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.

Structural insights into a cooperative switch between one and two FimH bacterial adhesins binding pauci- and high-mannose type N-glycan receptors.,Krammer EM, Bridot C, Serna S, Echeverria B, Semwal S, Roubinet B, van Noort K, Wilbers RHP, Bourenkov G, de Ruyck J, Landemarre L, Reichardt N, Bouckaert J J Biol Chem. 2023 May;299(5):104627. doi: 10.1016/j.jbc.2023.104627. Epub 2023 , Mar 20. PMID:36944399^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Krammer EM, Bridot C, Serna S, Echeverria B, Semwal S, Roubinet B, van Noort K, Wilbers RP, Bourenkov G, de Ruyck J, Landemarre L, Reichardt N, Bouckaert J. Structural insights into a cooperative switch between one and two FimH bacterial J Biol Chem. 2023 Mar 19:104627. PMID:36944399 doi:10.1016/j.jbc.2023.104627