Structural basis of virion assembly in the Mycobacterium tuberculosis –infecting mycobacteriophage SWU1

Abstract

The rising threat of drug–resistant tuberculosis has renewed interest in bacteriophage therapy as an urgently needed alternative. Rational engineering of these viruses, however, requires an atomic-level understanding of virion architecture. Mycobacteriophage SWU1 belongs to subcluster A2, one of the few mycobacteriophage lineages known to infect Mycobacterium tuberculosis ( M. tuberculosis ). Using single-particle cryogenic electron microscopy (cryo-EM), we resolved essentially the entire SWU1 virion architecture by localized reconstruction of four modules, the capsid, portal vertex, tail and baseplate, at resolutions of 3.62 Å, 3.51 Å, 3.70 Å and 3.22 Å, respectively. The T=7 capsid comprises 415 copies of an HK97-fold major capsid protein and lacks any decoration protein in density. The 12–fold portal reconciles its C5–C12 mismatch with the capsid vertex through defined, non-equivalent subunit contacts. The baseplate carries a 13-fold tail-fiber ring on a 6-fold hub, a geometry without precedent among characterized phages, established here by symmetry-free reconstruction. These findings provide the critical insights into the assembly and infection of SWU1, laying a structural foundation for the future optimization of phage-based anti-TB therapeutics.

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