Structures of Native Doublet Microtubules from Reveal Parasite-Specific Proteins as Potential Drug Targets.

Doublet microtubules (DMTs) are flagellar components required for the protist ( ) to swim through the human genitourinary tract to cause trichomoniasis, the most common non-viral sexually transmitted disease. Lack of DMT structures has prevented structure-guided drug design to manage infection. Here, we determined the cryo-EM structure of native DMTs, identifying 29 unique proteins, including 18 microtubule inner proteins and 9 microtubule outer proteins. While the A-tubule is simplistic compared to DMTs of other organisms, the B-tubule features specialized, parasite-specific proteins, like FAP40 and FAP35 that form filaments near the inner and outer junctions, respectively, to stabilize DMTs and enable locomotion. Notably, a small molecule, assigned as IP6, is coordinated within a pocket of FAP40 and has characteristics of a drug molecule. This first atomic model of the -DMT highlights the diversity of eukaryotic motility machinery and provides a structural framework to inform the rational design of therapeutics.