Navarra Giulio, Zihlmann Pascal, Jakob Roman P, Stangier Katja, Preston Roland C, Rabbani Said, Smiesko Martin, Wagner Bea, Maier Timm, Ernst Beat
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland.
Chembiochem. 2017 Mar 16;18(6):539-544. doi: 10.1002/cbic.201600615. Epub 2017 Feb 7.
Uropathogenic E. coli exploit PapG-II adhesin for infecting host cells of the kidney; the expression of PapG-II at the tip of bacterial pili correlates with the onset of pyelonephritis in humans, a potentially life-threatening condition. It was envisaged that blocking PapG-II (and thus bacterial adhesion) would provide a viable therapeutic alternative to conventional antibiotic treatment. In our search for potent PapG-II antagonists, we observed an increase in affinity when tetrasaccharide 1, the natural ligand of PapG-II in human kidneys, was elongated to hexasaccharide 2, even though the additional Siaα(2-3)Gal extension is not in direct contact with the lectin. ITC studies suggest that the increased affinity results from partial desolvation of nonbinding regions of the hexasaccharide; this is ultimately responsible for perturbation of the outer hydration layers. Our results are in agreement with previous observations and suggest a general mechanism for modulating carbohydrate-protein interactions based on nonbinding regions of the ligand.
致病性大肠杆菌利用PapG-II黏附素来感染肾脏的宿主细胞；细菌菌毛尖端PapG-II的表达与人类肾盂肾炎的发病相关，肾盂肾炎是一种可能危及生命的疾病。据设想，阻断PapG-II（从而阻止细菌黏附）将为传统抗生素治疗提供一种可行的治疗选择。在我们寻找强效PapG-II拮抗剂的过程中，我们观察到，当人肾脏中PapG-II的天然配体四糖1延长为六糖2时，亲和力增加，尽管额外的Siaα(2-3)Gal延伸并不直接与凝集素接触。等温滴定量热法研究表明，亲和力的增加源于六糖非结合区域的部分去溶剂化；这最终导致了外层水化层的扰动。我们的结果与之前的观察结果一致，并提出了一种基于配体非结合区域调节碳水化合物-蛋白质相互作用的一般机制。
