Membrane Protein Biology

INFECTIOUS DISEASES / Virology

Research Interests

Structural Biology of Membrane Protein Systems; Chloride Intracellular Channels, plasmid fertility inhibition; structure based drug discovery for novel therapeutics for atherosclerosis, cancer and sepsis; deciphering the molecular basis of Indian traditional medicine used for cardio and cerebrovascular therapy work. Foldscope for teaching and research.

Description of Research

We aim to understand membrane protein systems that mediate complex biological processes and translate these for future therapies by using biochemistry, biophysics, enzymology, X-ray crystallography, structure-based drug discovery, cell-based assays tools and through institutional collaborations.

1) Vitamin-C recycling in human health and crop improvement: we aim to understand the structural basis of Vitamin-C recycling by dimorphic bifunctional dehydroascorbate (DHA) reductases (DHARs) that also act as ion channels. Highly conserved across species, these exist as soluble enzymes and as ion-channels when membrane is inserted. Human Chloride Intracellular Channels (CLICs) come under this class of proteins which are overexpressed in many cancers. In addition to targeting high-resolution ionchannel structure, we explore both forms of HsCLICs as novel anti-cancer targets for discovery of small molecular inhibitors and plant DHARs (CLICs) for crop improvement. We also work on Monodehydro ascorbate (MDHA) reductase (MDHAR) enzyme that recycles Vitamin-C from MDHA in plants.

Structure based inhibitor discovery for Atherosclerosis: Ox-LDL plays a vital role in the development of atherosclerosis and other cardio and cerebrovascular diseases. Lectin-like oxidized low-density lipoprotein receptor1 (LOX-1) is a scavenger receptor predominantly expressed on the vascular endothelial cell surface and aids in binding and internalisation of oxidized low-density lipoproteins (Ox-LDL), resulting in plaque formation in the arteries and further pathology of atherosclerosis. We screen, design and validate small molecules that target Ox-LDL binding to LOX-1 for novel therapeutics to treat cardio cerebrovascular diseases, and have recently initiated a new programme to decipher the molecular mechanism of action of Indian traditional medicines used in cardiovascular therapy, using modern biological tools.

Plasmid fertility inhibition (FIN) systems: We try to understand the molecular mechanisms of diverse strategies used by competing conjugative self-transmissible plasmids to block the translocation of rival DNA at the respective type IV secretion system (T4SS). Our long-term goal is to develop therapeutics targeting T4SS to intervene in the emergence of antibiotic resistance in bacteria through horizontal gene transfer.

Novel antibiotic discovery for sepsis: Sepsis mediating bacterial pathogens are especially rampant in neonates and immunocompromised adults. With the emergence of MDR and XDR types, treatment in clinics and hospitals has become challenging, leading to increased morbidity and mortality. Targeting septicaemia with empirical broad-spectrum antibiotics has only led to selection of resistant mutants within the infecting pathogen pool. To reduce the emergence of antimicrobial resistance, targeting essential virulence proteins is an upcoming strategy. We are exploring outer membrane phospholipase A (OMPLA) of Acinetobacter baumannii and Klebsiella pneumoniae for novel antibiotics discovery.

Foldscope for tracking crystallization and imaging: As part of the Department of Biotechnology, Government of India outreach programme, we are taking Foldscopes to schools and colleges in the country for teaching crystallization and imaging.

Dimorphic and bi-functional CLICs are overexpressed in various cancers and are highly conserved across species.

Publications

Babu, K.,  Arulandu, A., Sankaran, K.  2017. The structure of DLP12 endolysin exhibiting alternate loop conformation and comparative analysis with other endolysins. Proteins 86, 210-217 PubMed link

Pothineni, N.V.K.,  Karathanasis, S.K., Ding, Z., Arulandu, A., Varughese, K.I., Mehta, J.L.  2017. LOX-1 in Atherosclerosis and Myocardial Ischemia: Biology, Genetics, and Modulation. J Am Coll Cardiol 69, 2759-2768 PubMed link

Krishna Das, B., Kumar, A., Maindola, P., Mahanty, S., Jain, S.K., Reddy, M. K., Arockiasamy, A. 2016. Non-native ligands define the active site of Pennisetum glaucum (L.) R. Br dehydroascorbate reductase. BiochemBiophys Res Commun 473, 1152-1157 PubMed link

Verma, A., Chandele, A., Nayak, K., Kaja, M. K., Arulandu, A., Lodha, R.,  Ray, P.  2016. High yield expression and purification of Chikungunya virus E2 recombinant protein and its evaluation for serodiagnosis. J Virol Methods 235, 73–79 PubMed link

Balasubramaniam, D., Arockiasamy, A., Kumar, P. D., Sharma, A., Krishnaswamy, S. 2012. Asymmetric pore occupancy in crystal structure of OmpF porin from Salmonella typhi. J Struct Biol 178, 233-244 PubMed link

Maindola, P., Raina, R., Goyal, P., Atmakuri, K., Ojha, A., Gupta, S., Christie, P.J., Iyer, L.M., Aravind, L., Arockiasamy, A. 2014. Multiple enzymatic activities of ParB/Srx superfamily mediate sexual conflict among conjugative plasmids. Nature Commun 5, 5322 PubMed link