Structure–Activity Relationship Study Reveals the Molecular Basis for Specific Sensing of Hydrophobic Amino Acids by the Campylobacter jejuni Chemoreceptor Tlp3

Biomolecules

Cengiz Koç¹  Anna Roujeinikova¹  MohammadF. Khan¹  MohammadM. Rahman¹  MayraA. Machuca¹  BrianJ. Smith²  RaymondS. Norton³ 

[1] Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Victoria 3800, Australia;La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia;Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;

关键词: Campylobacter jejuni;    chemoreceptor;    methyl-accepting chemotaxis protein;    dCache;    high-throughput screening;   

DOI  :  10.3390/biom10050744

来源: DOAJ

【 摘 要 】

Chemotaxis is an important virulence factor of the foodborne pathogen Campylobacter jejuni. Inactivation of chemoreceptor Tlp3 reduces the ability of C. jejuni to invade human and chicken cells and to colonise the jejunal mucosa of mice. Knowledge of the structure of the ligand-binding domain (LBD) of Tlp3 in complex with its ligands is essential for a full understanding of the molecular recognition underpinning chemotaxis. To date, the only structure in complex with a signal molecule is Tlp3 LBD bound to isoleucine. Here, we used in vitro and in silico screening to identify eight additional small molecules that signal through Tlp3 as attractants by directly binding to its LBD, and determined the crystal structures of their complexes. All new ligands (leucine, valine, α-amino-N-valeric acid, 4-methylisoleucine, β-methylnorleucine, 3-methylisoleucine, alanine, and phenylalanine) are nonpolar amino acids chemically and structurally similar to isoleucine. X-ray crystallographic analysis revealed the hydrophobic side-chain binding pocket and conserved protein residues that interact with the ammonium and carboxylate groups of the ligands determine the specificity of this chemoreceptor. The uptake of hydrophobic amino acids plays an important role in intestinal colonisation by C. jejuni, and our study suggests that C. jejuni seeks out hydrophobic amino acids using chemotaxis.

【 授权许可】

Unknown