Protein-Protein Interactions (PPIs) is the Holy Grail of therapeutic intervention, offering a plethora of unique structural landscapes as potential targets. I use structure-guided approaches to characterize and validate these interactions in the context of disease models. We utilize a combination of techniques including NMR spectroscopy, NMR-based fragment and high throughput screening, and biophysical and cell-based assays to map hotspots in the interaction interface, to further understand the molecular mechanisms orchestrated by these interactions, and to identify disruptive inhibitors that may be developed into treatments for the related pathologies. Our current areas of focus are 1) the critical interactions between transcription factors and the general transcriptional machinery, including the Mediator complex, co-activators, and remodeling factors, and 2) translation initiation machinery demonstrated to be dysregulated in cancer disease states. We are working on making use of NMR-derived metabolomics data in the identification of novel metabolite disease markers that in combination with cellular pathway analysis can be used to identify new potential therapeutic targets. In order to facilitate our research goals, we also work on the development of new NMR methods for fragment screening, metabolite fingerprinting and protein-ligand interaction identification. Our work on novel pulse sequences, pulse designs, labeling strategies and sampling schemes let us push the boundaries of NMR as a technique, allowing us to tackle larger systems by NMR.
1) Thakur JK*, Arthanari H*, Yang F*, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 2008. 452 (7187): 604-9.
2) Frueh DP, Arthanari H, Koglin A, Vosburg DA, Bennett AE, Walsh CT, Wagner G. Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase. Nature 2008. 454 (7206)
3)Luna RE*, Arthanari H*, Hiraishi H, Nanda J, Martin-Marcos P, Markus MA, Akabayov B, Milbradt AG, Luna LE, Seo HC, Hyberts SG, Fahmy A, Reibarkh M, Miles D, Hagner PR, O'Day EM, Yi T, Marintchev A, Hinnebusch AG, Lorsch JR, Asano K, Wagner G. The C-Terminal Domain of Eukaryotic Initiation Factor 5 Promotes Start Codon Recognition by Its Dynamic Interplay with eIF1 and eIF2β. Cell Rep. 2012 Jun 28;1(6):689-702
4) Arthanari H, Wagner G, Khaneja N. Heteronuclear decoupling by multiple rotating frame technique. J Magn Reson. 2011 Mar;209(1):8-18.
5) Schmidt JC, Arthanari H*, Boeszoermenyi A*, Dashkevich NM*, Wilson-Kubalek EM*, Monnier N, Markus M,Oberer M, Milligan RA, Bathe M,Wagner G, Grishchuk EL, Cheeseman IM. The kinetochore-bound Ska1 complex tracks depolymerizing microtubules by binding to curved protofilaments. Dev Cell. 2012 Nov 13;23(5):968-80
6) Coote P, Leigh KE, Yu TY, Khaneja N, Wagner G, Arthanari H. A new broadband homonuclear mixing pulse for NMR with low applied power. J Chem Phys. 2014 Jul 14;141(2):024201.