Dr. Ashwani Sharma

Scientist
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Biography
Ashwani completed his doctoral studies at ICGEB (New Delhi India), on a project that aimed at the structural and functional characterization of malaria parasite proteins involved in crosstalk with the human cell components. He performed his postdoctoral research at PSI and then at EPFL where he successfully applied a combination of structural and biophysical techniques to study mammalian tubulin-protein and tubulin-drug complexes. Subsequently, with the support from a Novartis FreeNovation grant and a SNF Spark grant, he initiated a project together with Dr. Natacha Gaillard on the Apicomplexan microtubule cytoskeleton at PSI. Additionally, Ashwani is leading and managing Biophysics Resources at PSI (https://www.psi.ch/en/lbr/facilities).
Research Interests
Eukaryotic parasites belonging to the phylum Apicomplexa invade host cells via a complex and active process which involves the coordinated action of multiple organelles located at the apical end of the parasites (apical complex, APC). The APC comprises of a tubulin based conoid, multiple secretory organelles (rhoptries and micronemes) and inter-conoidal microtubules (MTs). Although, the APC is implicated in parasite invasion by secreting parasite proteins into the host cells, to date, molecular details of the role of the MTs in APC secretion and host cell invasion remains largely unknown. Towards this end, we are using recombinant protein technologies in combination with biochemical and structural methods to discover the interactions of host and parasite MTs with the parasite proteins involved in host cell invasion.
Inhibition of cell division by using tubulin targeting, antimitotic compounds has been the most successful strategy for cancer treatment up to now. Implementing a similar strategy to arrest parasite replication using apicomplexan tubulin specific inhibitors offers a completely new and attractive avenue towards anti-apicomplexan drug discovery. Our research interest is to exploit the structural peculiarities of apicomplexan tubulin drug-binding sites in comparison to their mammalian counterparts to develop novel anti-tubulin drugs specific for protozoan parasites.
Grants/Awards
AIMS Award, Principal Investigator
Award from Atomwise Inc. for AI based anti-parasite drug discovery
Spark, SNF, Principal Investigator
Host cytoskeleton manipulation by Apicomplexan parasites: structural and functional investigation of the RON complex
Novartis Freenovation Grant, Co-Principal Investigator
Towards the Structure Based Design of Broad Spectrum Anti-Apicomplexan Drugs
EMBO Long Term Fellowship
Publications
-
Mühlethaler T, Olieric N, Ehrhard VA, Wranik M, Standfuss J, Sharma A, et al.
Crystallization systems for the high-resolution structural analysis of tubulin-ligand complexes
In: Inaba H, ed. Microtubules. Methods and protocols. Methods in molecular biology. New York: Humana Press; 2022:349-374. https://doi.org/10.1007/978-1-0716-1983-4_23
DORA PSI -
Gaillard N, Sharma A, Abbaali I, Liu T, Shilliday F, Cook AD, et al.
Inhibiting parasite proliferation using a rationally designed anti-tubulin agent
EMBO Molecular Medicine. 2021; 13(11): e13818 (12 pp.). https://doi.org/10.15252/emmm.202013818
DORA PSI -
Sharma A, Olieric N, Steinmetz MO
Centriole length control
Current Opinion in Structural Biology. 2021; 66: 89-95. https://doi.org/10.1016/j.sbi.2020.10.011
DORA PSI -
Kashyap AS, Fernandez-Rodriguez L, Zhao Y, Monaco G, Trefny MP, Yoshida N, et al.
GEF-H1 signaling upon microtubule destabilization is required for dendritic cell activation and specific anti-tumor responses
Cell Reports. 2019; 28(13): 3367-3380.e1. https://doi.org/10.1016/j.celrep.2019.08.057
DORA PSI -
La Sala G, Olieric N, Sharma A, Viti F, de Asis Balaguer Perez F, Huang L, et al.
Structure, thermodynamics, and kinetics of plinabulin binding to two tubulin isotypes
Chem. 2019; 5(11): 2969-2986. https://doi.org/10.1016/j.chempr.2019.08.022
DORA PSI -
Aher A, Kok M, Sharma A, Rai A, Olieric N, Rodriguez-Garcia R, et al.
CLASP suppresses microtubule catastrophes through a single TOG domain
Developmental Cell. 2018; 46(1): 40-58.e8. https://doi.org/10.1016/j.devcel.2018.05.032
DORA PSI -
Sharma A, Gerard SF, Olieric N, Steinmetz MO
Cep120 promotes microtubule formation through a unique tubulin binding C2 domain
Journal of Structural Biology. 2018; 203(1): 62-70. https://doi.org/10.1016/j.jsb.2018.01.009
DORA PSI -
Sharma A, Sáez-Calvo G, Olieric N, de Asís Balaguer F, Barasoain I, Lamberth C, et al.
Quinolin-6-yloxyacetamides are microtubule destabilizing agents that bind to the colchicine site of tubulin
International Journal of Molecular Sciences. 2017; 18(7): 1336 (11 pp.). https://doi.org/10.3390/ijms18071336
DORA PSI -
Sáez-Calvo G, Sharma A, de Asís Balaguer F, Barasoain I, Rodríguez-Salarichs J, Olieric N, et al.
Triazolopyrimidines are microtubule-stabilizing agents that bind the vinca inhibitor site of tubulin
Cell Chemical Biology. 2017; 24(6): 737-750. https://doi.org/10.1016/j.chembiol.2017.05.016
DORA PSI -
Burger D, Stihle M, Sharma A, Di Lello P, Benz J, D'Arcy B, et al.
Crystal structures of the human doublecortin C- and N-terminal domains in complex with specific antibodies
Journal of Biological Chemistry. 2016; 291(31): 16292-16306. https://doi.org/10.1074/jbc.M116.726547
DORA PSI -
Sharma A, Aher A, Dynes NJ, Frey D, Katrukha EA, Jaussi R, et al.
Centriolar CPAP/SAS-4 imparts slow processive microtubule growth
Developmental Cell. 2016; 37(4): 362-376. https://doi.org/10.1016/j.devcel.2016.04.024
DORA PSI -
Kashyap M, Sharma A, Bhavesh NS
Purification, crystallization and preliminary crystallographic studies of C-terminal RNA recognition motif (RRM-3) of human ELAV-type RNA-binding protein 3 (ETR-3)
Acta Crystallographica Section F: Structural Biology and Crystallization Communications. 2013; 69(10): 1107-1109. https://doi.org/10.1107/S1744309113023439
DORA PSI
-
Purification, crystallization and preliminary crystallographic studies of C-terminal RNA recognition motif (RRM-3) of human ELAV-type RNA-binding protein 3 (ETR-3).
Acta Crystallogr Sect F Struct Biol Cryst Commun. 69(Pt 10), 1107-09 (2013).DOI: http://dx.doi.org/10.1107/S1744309113023439.
-
Utility of anion and cation combinations for phasing of protein structures.
J Struct Funct Genomics. 13(3), 135-43 (2012).DOI: http://dx.doi.org/10.1007/s10969-012-9137-3.
-
Fatty acid induced remodeling within the human liver fatty acid-binding protein.
J Biol Chem. 286(36), 31924-8 (2011).DOI: http://dx.doi.org/10.1074/jbc.M111.270165.
-
Structural insights into thioredoxin-2:a component of malaria parasite protein secretion machinery.
Scientific Reports 1:179, (2011).DOI: http://dx.doi.org/10.1038/srep00179.
-
Crystal structure of soluble domain of malaria sporozoite protein UIS3 in complex with lipid.
J Biol Chem. 283(35), 24077-88 (2008).DOI: http://dx.doi.org/10.1074/jbc.M801946200.
-
Role of Plasmodium falciparum thrombospondin-related anonymous protein in host-cell interactions.
Malar J. 7:63, (2008).DOI: http://dx.doi.org/10.1186/1475-2875-7-63.