Atomic resolution structure of human papillomavirus bound to heparin

Human papillomavirus (HPV) is a significant health burden and leading cause of virus-induced cancers. The mechanisms of HPV receptor binding and host entry are not completely understood, although it is known that heparan sulfate proteoglycans (HSPGs) mediate entry. HPV16 quasivirus, composed of L1 and L2 capsid proteins with a packaged cottontail rabbit papillomavirus genome was incubated with heparin. The complex was vitrified, and data were collected for cryoEM single particle analysis. Subparticles were extracted and hexavalent and pentavalent capsomers were refined separately. Here we present the resulting 1.9 Å resolution structure, with heparin visualized around the capsomer at the icosahedral fivefold vertex. A model of the asymmetric unit was built unambiguously into the atomic resolution cryoEM map. Hydrogen bonds are predicted between L1 N-terminal regions, which are supported by molecular dynamics. The heparin binding site was identified, along with local L1 conformational changes and global flexibility changes. These changes induced by heparin binding likely reflect the structure of HPV during early stages of entry and provide a framework for future HPV biochemical, genetic, and biophysical studies. Human papillomavirus (HPV) is a significant health burden, but the mechanisms of HPV receptor binding are not understood. Here, the authors solve a 1.9 Å resolution structure of HPV bound to heparin with insights into the binding interface.