RMSD analysis of structures of the bacterial protein FimH identifies five conformations of its lectin domain

Abstract

FimH is a bacterial adhesin protein located at the tip of Escherichia coli fimbria that functions to adhere bacteria to host cells. Thus, FimH is a critical factor in bacterial infections such as urinary tract infections and is of interest in drug development. It is also involved in vaccine development and as a model for understanding shear‐enhanced catch bond cell adhesion. To date, over 60 structures have been deposited in the Protein Data Bank showing interactions between FimH and mannose ligands, potential inhibitors, and other fimbrial proteins. In addition to providing insights about ligand recognition and fimbrial assembly, these structures provide insights into conformational changes in the two domains of FimH that are critical for its function. To gain further insights into these structural changes, we have superposed FimH's mannose binding lectin domain in all these structures and categorized the structures into five groups of lectin domain conformers using RMSD as a metric. Many structures also include the pilin domain, which anchors FimH to the fimbriae and regulates the conformation and function of the lectin domain. For these structures, we have also compared the relative orientations of the two domains. These structural analyses enhance our understanding of the conformational changes associated with FimH ligand binding and domain‐domain interactions, including its catch bond behavior through allosteric action of force in bacterial adhesion.

Binding site plasticity regulation of the FimH catch-bond mechanism

“…2 presents the three main states of the lectin domain that are relevant to fimbrial adhesion and will serve as the basis to our study. They correspond respectively to groups 1, 4 and 3 in Magala et al 45 (group 2 comes from a single NMR study and is nearly identical to group 1, and group 5 corresponds to a structure of the pilial tip in complex with the usher FimD, 46 thus mostly relevant to pilial assembly pathway in the outer membrane):…”

“…FimH displays notable conformational diversity, found among more than 60 structures published in the Protein Data Bank (PDB), and ranging from the lectin domain alone to the full fimbrial tip assembly, either in presence or absence of mannose-derivated ligands. As shown in a recent work based on a pairwise RMSD analysis from Magala et al, 45 most of the intra-domain plasticity is found in the binding (lectin) domain and can be clustered in a set of five conformers. These conformers have been inconsistently labeled in the literature, using adjectives alternatively referring to the binding-site conformation (“open” or “closed”, “loose” or “tight”, “wide” or “narrow”), the lectin-domain overall shape (“elongated” or “compressed”), the interaction with the pilin domain (“Associated (A)” or “Separated (S)”), the presence of a ligand (“free” or “bound”) or the inferred binding affinity corresponding to that state (“low affinity” or “high affinity”, “relaxed (R)” or “tense (T)” – by analogy with traditional allosteric nomenclature).…”

“…Interdomain plasticity consists of one well-defined Associated conformation, where the two domains are in close interaction, and an ensemble of nonspecific poses where the domains have little to no interaction and orient themselves freely thanks to the flexibility of the linker. 28,45…”

“…Interdomain plasticity consists of one well-defined Associated conformation, where the two domains are in close interaction, and an ensemble of nonspecific poses where the domains have little to no interaction and orient themselves freely thanks to the flexibility of the linker. 28,45 Fig. 2 presents the three main states of the lectin domain that are relevant to fimbrial adhesion and will serve as the basis to our study.…”

A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis

“…The pilin and lectin domains of FimH together exist in an equilibrium between tense and relaxed states with differential mannose binding affinity. Conversion between these states is governed in part by a catch-bond mechanism [9,[42][43][44]. In the relaxed state, the FimH lectin domain samples conformational ensembles, allowing it to act as a molecular tether, with the mannose binding pocket in a conformation able to bind mannose tightly; in the tense state, the pocket is open and thus binds mannose only weakly [8].…”