Sager Christoph P, Fiege Brigitte, Zihlmann Pascal, Vannam Raghu, Rabbani Said, Jakob Roman P, Preston Roland C, Zalewski Adam, Maier Timm, Peczuh Mark W, Ernst Beat
University of Basel , Institute of Molecular Pharmacy , Pharmacenter of the University of Basel , Klingelbergstrasse 50 , 4056 , Basel , Switzerland . Email:
Department of Chemistry , University of Connecticut , 55 N. Eagleville Road U3060, Storrs , CT , 06279 USA . Email:
Chem Sci. 2017 Nov 8;9(3):646-654. doi: 10.1039/c7sc04289b. eCollection 2018 Jan 21.
Seven-membered ring mimetics of mannose were studied as ligands for the mannose-specific bacterial lectin FimH, which plays an essential role in the first step of urinary tract infections (UTI). A competitive binding assay and isothermal titration calorimetry (ITC) experiments indicated an approximately ten-fold lower affinity for the seven-membered ring mannose mimetic 2--heptyl-1,6-anhydro-d--d-galactitol () compared to -heptyl α-d-mannopyranoside (), resulting exclusively from a loss of conformational entropy. Investigations by solution NMR, X-ray crystallography, and molecular modeling revealed that establishes a superimposable H-bond network compared to mannoside , but at the price of a high entropic penalty due to the loss of its pronounced conformational flexibility. These results underscore the importance of having access to the complete thermodynamic profile of a molecular interaction to "rescue" ligands from entropic penalties with an otherwise perfect fit to the protein binding site.
七元环甘露糖类似物作为甘露糖特异性细菌凝集素FimH的配体进行了研究，FimH在尿路感染（UTI）的第一步中起着至关重要的作用。竞争性结合试验和等温滴定量热法（ITC）实验表明，与庚基α-d-甘露吡喃糖苷（）相比，七元环甘露糖类似物2-庚基-1,6-脱水-d-半乳糖醇（）的亲和力低约十倍，这完全是由于构象熵的损失所致。通过溶液核磁共振、X射线晶体学和分子建模进行的研究表明，与甘露糖苷相比，建立了一个可叠加的氢键网络，但由于其明显的构象灵活性丧失而付出了高熵代价。这些结果强调了获得分子相互作用的完整热力学概况对于从熵惩罚中“拯救”配体的重要性，否则配体与蛋白质结合位点完美契合。
