7PJF

Inhibiting parasite proliferation using a rationally designed anti-tubulin agent

Summary for 7PJF

• Entry DOI: 10.2210/pdb7pjf/pdb
• Descriptor: Tubulin alpha-1B chain, Tubulin beta-3 chain, Designed ankyrin repeat protein (DARPIN) D1, ... (6 entities in total)
• Functional Keywords: tubulin, microtubules, protozoa, apicomplexa, structural protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 118443.84

Authors

Sharma, A.,Gaillard, N.,Ehrhard, V.A.,Steinmetz, M.O. (deposition date: 2021-08-24, release date: 2021-09-22, Last modification date: 2024-01-31)

Primary citation

Gaillard, N.,Sharma, A.,Abbaali, I.,Liu, T.,Shilliday, F.,Cook, A.D.,Ehrhard, V.,Bangera, M.,Roberts, A.J.,Moores, C.A.,Morrissette, N.,Steinmetz, M.O.
Inhibiting parasite proliferation using a rationally designed anti-tubulin agent.
Embo Mol Med, 13:e13818-e13818, 2021

PubMed Abstract: Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand-binding sites in tubulin makes this protein an attractive target for anti-parasite drug discovery. However, despite remarkable successes as anti-cancer agents, the rational development of protozoan parasite-specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug-binding sites. Based on this information, we rationally designed the parasite-specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species-specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much-needed, novel parasite inhibitors.

PubMed: 34661376
DOI: 10.15252/emmm.202013818

Experimental method

X-RAY DIFFRACTION (1.862 Å)