Structural and mechanistic investigations of histone like DNA binding protein (Hup) of <i>Helicobacter pylori</i>
Creators: name: Jaiswal, Nancy
name: Raikwal, Nisha
name: Himanshu Pandey
name: Arora, Ashish
name: Anirban Ghosh
name: Anirban Bhunia
name: Khushboo Gulati
name: Krishnakant Gangele
name: Krishna.M Poluri
name: Kumar, Dinesh
Publisher: name: F1000Research
Year: 2016

description: <i>Helicobacter pylori</i> (<i>H. pylori</i>) is a human gastric pathogen and is an established cause of several gastric pathologies including chronic gastritis, duodenal/peptic ulcers, and gastric cancer [1,2]. The pathogen colonizes under harsh acidic and oxidative stress conditions of human stomach and can survive there for infinitely longer durations of host life. This happens because of several harbinger proteins the bacterium expresses to facilitate its persistent colonization under such harsh conditions. One such protein in <i>H. pylori</i> is the Histone like DNA binding protein –referred here as Hup– which is remarkable in terms of its capabilities to perform both the architectural as well as regulatory functions [3]. It serves to maintain genome integrity at different stages of the bacterial life cycle and also plays a pivotal role in the formation of a sturdy nucleoid structure which helps protecting <i>H. pylori</i> DNA from physical damage and to some extent from acidic denaturation under gastric conditions [3]. In addition, it participates in all DNA-dependent cellular activities, including, replication, recombination, repair and transcription. Overall, the protein provides an additional mechanism for <i>H. pylori</i> to survive and colonize persistently under harsh conditions of human stomach characterized by acidity, peristalsis, and attack by phagocytes accompanied by release of reactive oxygen species (ROS) [3-5]. Therefore, suppressing the activity of Hup by the application of inhibitors has been recognized as a promising mean to limit the <i>H. pylori</i> infection in humans [3,6]. The inhibitors can be designed timely and in a cost effective manner following the rational structure based drug discovery approach. However, to inhibit the functioning of Hup, first it is necessary to gain a clear understanding of its structure and DNA-binding mechanism. So far, there is no literature reported on the high-resolution structures of Hup-dimer and its DNA binding modes. Further as reported for other proteins of this class, the molecular basis of its oligomerization behaviour and its role in DNA stabilization has not been studied in physiologically relevant solution conditions. This derived our interest to study the mechanistic and structural biology of this medically important protein and thus to unravel the molecular basis of its oligomerization and DNA binding interaction using versatility of NMR coupled with various other chemical-biology tools. The resulted structural information would help to guide the rational discovery of small-molecule inhibitors which could be taken forward in the design of novel chemotherapeutic agents against <i>H. pylori</i>.<br><br><br>References:<br><br>[1] B.E. Dunn, H. Cohen, M.J. Blaser, Helicobacter pylori, Clin. Microbiol. Rev 10 (1997) 720-741.<br>[2] F.K. Chan, K.F. To, J.C. Wu, M.Y. Yung, W.K. Leung, T. Kwok, Y. Hui, H.L. Chan, C.S. Chan, E. Hui, Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial, The Lancet 359 (2002) 9-13.<br>[3] G. Wang, L.F. Lo, R.J. Maier, A histone-like protein of Helicobacter pylori protects DNA from stress damage and aids host colonization, DNA Repair (Amst) 11 (2012) 733-740.<br>[4] G. Wang, P. Alamuri, R.J. Maier, The diverse antioxidant systems of Helicobacter pylori, Mol Microbiol. 61 (2006) 847-860.<br>[5] E.J. O'Rourke, C. Chevalier, A.V. Pinto, J.M. Thiberge, L. Ielpi, A.s. Labigne, J.P. Radicella, Pathogen DNA as target for host-generated oxidative stress: Role for repair of bacterial DNA damage in Helicobacter pylori colonization, Proceedings of the National Academy of Sciences 100 (2003) 2789-2794.<br>[6] C. Chen, S. Ghosh, A. Grove, Substrate specificity of Helicobacter pylori histone-like HU protein is determined by insufficient stabilization of DNA flexure points, Biochem. J. 383 (2004) 343-351.