Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection
Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection
复制标题
DOI：
10.1046/j.1365-2958.2002.02915.x
复制
发表时间：
2002-05-01
影响因子：
3.6
通讯作者：
Hultgren, SJ
中科院分区：
文献类型：
--
作者：
Hung, CS;Bouckaert, J;Hultgren, SJ
致病性大肠杆菌在人泌尿道定殖的第一步是FimH（存在于1型皮利尖端的粘附素）与膀胱上皮的甘露糖敏感性结合。我们从晶体学上阐明了FimH与D-甘露糖的相互作用。使用定点诱变探测由D-甘露糖占据的独特位点结合口袋。除了一个突变体外，所有检测的突变体都大大降低了甘露糖结合活性，并且也失去了结合人类膀胱细胞的能力。单糖D-甘露糖的结合活性是通过产生消除D-甘露糖结合但保留甘露三糖结合活性的突变体而从甘露三糖（Man（α 1 -3）[Man（α 1 -6）]Man）中描绘出来的。我们的结构/功能分析表明，单糖α-D-甘露糖的结合是尿路致病性大肠杆菌的主要膀胱细胞受体。大肠杆菌中，这一事件需要一个高度保守的FimH结合口袋。对FimH甘露糖结合口袋中的残基进行了测序，发现在200多个尿路致病性大肠杆菌菌株中是不变的。杆菌只有肠出血性E.大肠杆菌（EHEC）的FimH的甘露糖结合口袋内具有序列变异，表明EHEC细菌中天然存在的减毒机制，这将阻止它们靶向泌尿道。
The first step in the colonization of the human urinary tract by pathogenic Escherichia coli is the mannose-sensitive binding of FimH, the adhesin present at the tip of type 1 pili, to the bladder epithelium. We elucidated crystallographically the interactions of FimH with D-mannose. The unique site binding pocket occupied by D-mannose was probed using site-directed mutagenesis. All but one of the mutants examined had greatly diminished mannose-binding activity and had also lost the ability to bind human bladder cells. The binding activity of the mono-saccharide D-mannose was delineated from this of mannotriose (Man(alpha1-3)[Man(alpha1-6)]Man) by gener-ating mutants that abolished D-mannose binding but retained mannotriose binding activity. Our structure/function analysis demonstrated that the binding of the monosaccharide alpha-D-mannose is the primary bladder cell receptor for uropathogenic E. coli and that this event requires a highly conserved FimH binding pocket. The residues in the FimH mannose-binding pocket were sequenced and found to be invariant in over 200 uropathogenic strains of E. coli . Only enterohaemorrhagic E. coli (EHEC) possess a sequence variation within the mannose-binding pocket of FimH, suggesting a naturally occurring mechanism of attenuation in EHEC bacteria that would prevent them from being targeted to the urinary tract.