The distinct trimeric structure of the immunodominant chlamydial antigen Major Outer Membrane Protein

The chlamydial Major Outer Membrane Protein (MOMP) is a promising subunit vaccine candidate due to its abundance in the outer membrane (OM), the presence of four surface-exposed variable domains (VDs) containing neutralizing and serotyping epitopes, and confirmed T-cell epitopes located in its constant domains (CDs). However, recombinant and denatured forms of MOMP have failed to elicit immune responses comparable to native preparations, indicating that conformation is critical for immunogenicity. Here, we present two cryo-EM structures of native Chlamydia muridarum MOMP, isolated from infectious elementary bodies (EBs). EB MOMP forms a distinct trimer with a stem of three narrow, non-permeable β-barrels and an extracellular, folded antigenic cap that displays VDs. In complex with a neutralizing Fab fragment of a conformational antibody, the cap undergoes structural reorganization that shows how epitope presentation is modulated by immune engagement. These structures reveal the molecular basis of MOMP’s serovar specificity and provide a template for structure-based vaccine design. Cryo-EM structures of native trimeric MOMP isolated from chlamydial infectious bodies show a distinct 10-stranded beta-barrel architecture that explains antibody recognition, disproves porin function, and guides structure-based vaccine design.