Abstract
The galactose specific lectin LecA mediates biofilm formation in the opportunistic pathogen P. aeruginosa . The interaction between LecA and aromatic β-galactoside biofilm inhibitors involves an intermolecular CH-π T-shape interaction between C(ε1)-H of residue His50 in LecA and the aromatic ring of the galactoside aglycone. The generality of this interaction was tested in a diverse family of β-galactosides. LecA binding to aromatic β-galactosides (KD ∼ 8 μM) was consistently stronger than to aliphatic β-galactosides (KD ∼ 36 μM). The CH-π interaction was observed in the X-ray crystal structures of six different LecA complexes, with shorter than the van der Waals distances indicating productive binding. Related XH/cation/π-π interactions involving other residues were identified in complexes of aromatic glycosides with a variety of carbohydrate binding proteins such as concanavalin A. Exploiting such interactions might be generally useful in drug design against these targets.
Highlights
Two parameters were measured: 1) The angle α between the normal of each plane spanned by an aromatic ring (0 – 90°) 2) The distance d between the centroid of the histidine ring and the normal line of the other aromatic ring ε1 δ1 N N ε2 γ δ2 α normal line to Histidine plane d normal line to aromatic plane π-stack
Total a) All unique histidine-aromatic residue or histidine-ligand aromatic ring pairs with centroid distance ≤ 5.0 Å are considered. b) The T-shape subcategories refer to the His ring atom closest to the centroid of the other aromatic ring. c) Aromatic residues: Phe, Tyr, Trp, His. d) Aromatic rings in ligands were identifed as planar 5-7 membered ring with C, N, O or S allowing ± 10° deviation from planarity. e) π-stack: α < 20°, d
Galactosides used in this study were the built using maestro interface and subsequently, geometry optimized by Macromodel program v9.1 (Schrodinger, LLC) using the Optimized Potentials for Liquid Simulations-all atom (OPLS-AA) force field[22] with the truncated Newton conjugate gradient protocol
Summary
CH-π “T-Shape” Interaction with Histidine Explains Binding of Aromatic Galactosides to Pseudomonas aeruginosa lectin LecA. His-aromatic contacts were identified with the condition that the distance between the centroid of the histidine imidazole ring and the centroid of the other aromatic ring (aromatic ring from side-chain or ligand) is less than 5.0 Å. Redundant pairs were identified as those having the same protein name and the same residue numbers. Two parameters were measured: 1) The angle α between the normal of each plane spanned by an aromatic ring (0 – 90°) 2) The distance d between the centroid of the histidine ring and the normal line of the other aromatic ring ε1 δ1 N N ε2 γ δ2 α normal line to Histidine plane d normal line to aromatic plane π-stack
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