Structure and Function of a Multi‐Megadalton Virus‐Like Proteolytic Dodecahedron

Natural pentamer dodecahedra (Ddhs) span six orders of magnitude in diameter. Among proteins, only two catalytic Ddhs have been structurally characterized: lumazine synthase (LS) and the core of pyruvate dehydrogenase (PDH). Zuzalysin (ZUZ) is a ≈95‐kDa metallopeptidase secreted for virulence by Porphyromonas gingivalis . Calcium converts latent flexible monomers into active ≈0.5‐MDa pentamers that further assemble hierarchically into bipentamers, tripentamers, and a ≈5.6‐MDa, ≈355‐Å virus‐like dodecahedron (Ddh ZUZ ). Experimental structures (1.8–3.6 Å) across these states reveal the molecular basis of activation, association, and catalysis, culminating in Ddh ZUZ , which is physiologic, exceeds small viral capsids, and has 20 main entry pores and 60 lumen‐facing active sites. ZUZ represents the largest catalytic protein assembly resolved at high resolution, exceeding LS, PDH, and major peptidase complexes in size and/or resolution.