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, such as 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 rational design of therapeutics.