Structures of Native Doublet Microtubules fromTrichomonas vaginalisReveal Parasite-Specific Proteins as Potential Drug Targets

Abstract

Doublet microtubules (DMTs) are flagellar components required for the protistTrichomonas vaginalis(Tv) 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 manageTvinfection. Here, we determined the cryo-EM structure of nativeTv-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, likeTvFAP40 andTvFAP35 that form filaments near the inner and outer junctions, respectively, to stabilize DMTs and enableTvlocomotion. Notably, a small molecule, assigned as IP6, is coordinated within a pocket ofTvFAP40 and has characteristics of a drug molecule. This first atomic model of theTv-DMT highlights the diversity of eukaryotic motility machinery and provides a structural framework to inform the rational design of therapeutics.