Elucidating the mechanism of pH‐gating, solute selectivity, and flux of UreI, the urea channel of Helicobacter pylori - Prof. Jakob Ulmschneider, Institute of Natural Sciences
Project:  Elucidating the mechanism of pH-gating, solute selectivity, and flux of UreI, the urea channel of Helicobacter pylori
Abstract:  We are studying the atomic detail mechanics driving pH-gating, solute selectivity, and flux of HpUreI, the urea channel crucial for survival of H. pylori at low pH. H. pylori remains a worldwide problem, contributing to peptic ulcer disease and gastric cancer. Without active intervention, at least 20% of the population of developed countries will continue to be infected. Current eradication requires triple therapy, a proton-pump inhibitor and two antibiotics given twice a day for 10 to 14 days. Resistance to either clarithromycin or metronidazole is > 20% and rising.
Gastric infection by Helicobacter pylori depends on the expression of a urea channel unique to this pathogen, UreI. This channel allows H. pylori to thrive in low pH environments by funneling urea to the cytoplasmic urease, where it is split into CO2 and 2NH3, which in turn are exported to buffer the pathogen’s periplasmic space. Our collaborators have recently succeeded in solving the crystal structure of UreI, which forms a completely new protein fold consisting of a hexameric ring of channel protomers surrounding a central lipid filled plug.
We use multi-microsecond simulations of the hexameric channel assembly to investigate the atomic detail mechanics that regulate pH-gating, solute selectivity, and flux limitation. In addition, we will study the export route and transport mechanisms of the urea hydrolysis products, CO2 and NH3, back into the periplasmic space. Inhibition of either urea or CO2 and NH3 transport would render H. pylori susceptible to acidic degradation, thus presenting a good opportunity for targeted drug development. A thorough understanding of the molecular mechanisms underlying channel function is vital for the design of suitable inhibitors and new therapies. Blocking of this channel would be expected to result in a specific and effective monotherapy for eradication of the organism. This would provide a preventive approach to serious upper gastro-intestinal diseases, particularly gastric cancer. Our studies require multi-microsecond simulations that are able to capture channel function of the native UreI homo-hexamer in a lipid bilayer. Simulations of systems of this size, and at the timescales required, are currently only feasible on large resources, such as HPC-SJTU, and have the potential to reveal the inner workings of a major drug target for one of the world’s most dangerous pathogens.
Research team: 
  1. Lead PI: Jakob Ulmschneider (INS)
  2. Postdoc: Sanjay Kumar Upadhyay (INS)
  3. Student: Yukun Wang (Life Science College)
Contact:  Dr. Jakob Ulmschneider, Institute of Natural Sciences, phone: 008615021946378, email: Jakob@sjtu.edu.cn
Room 522, Pao Yue-Kong Library (North Gate Entrance), Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240

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