Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Crystal Structures of Two Immune Complexes Identify Determinants for Viral Infectivity and Type-Specific Neutralization of Human Papillomavirus.
Journal, issue, pages	mBio, Vol. 8, Issue 5, Year 2017
Publish date	Sep 26, 2017
Authors	Zhihai Li / Daning Wang / Ying Gu / Shuo Song / Maozhou He / Jingjie Shi / Xinlin Liu / Shuangping Wei / Jinjin Li / Hai Yu / Qingbing Zheng / Xiaodong Yan / Timothy S Baker / Jun Zhang / Jason S McLellan / Shaowei Li / Ningshao Xia /
PubMed Abstract	Persistent, high-risk human papillomavirus (HPV) infection is the primary cause of cervical cancer. Neutralizing antibodies elicited by L1-only virus-like particles (VLPs) can block HPV infection; ...Persistent, high-risk human papillomavirus (HPV) infection is the primary cause of cervical cancer. Neutralizing antibodies elicited by L1-only virus-like particles (VLPs) can block HPV infection; however, the lack of high-resolution structures has limited our understanding of the mode of virus infection and the requirement for type specificity at the molecular level. Here, we describe two antibodies, A12A3 and 28F10, that specifically bind to and neutralize HPV58 and HPV59, respectively, through two distinct binding stoichiometries. We show that the epitopes of A12A3 are clustered in the DE loops of two adjacent HPV58 L1 monomers, whereas 28F10 recognizes the HPV59 FG loop of a single monomer. Via structure-based mutagenesis and analysis of antibody binding, we further identified the residues HPV58 D154, S168, and N170 and HPV59 M267, Q270, E273, Y276, K278, and R283, which play critical roles in virus infection. By substituting these strategic epitope residues into other HPV genotypes, we could then redirect the type-specific binding of the antibodies to these genotypes, thus highlighting the importance of these specific residues, HPV58 R161, S168, and N308 and HPV59 Q270, E273, and D281. Overall, our findings provide molecular insights into potential structural determinants of HPV required for infectivity and type specificity. High-risk human papillomaviruses (HPVs) are considered the major causative pathogens of cancers that affect epithelial mucosa, such as cervical cancer. However, because of the lack of high-resolution structural information on the sites of neutralization, we have yet to determine the precise mode of HPV infection and how different types of HPV cause infection. Our crystal structures in this study have uncovered discrete binding stoichiometries for two different antibodies. We show that one A12A3 Fab binds to the center of one HPV58 pentamer, whereas five 28F10 Fabs bind along the top fringe of one HPV59 pentamer. Furthermore, through targeted epitope analysis, we show that 6 to 7 discontinuous residues of the L1 major capsid protein of HPV are determinants, at least in part, for virus infection and type specificity. This knowledge will help us to unravel the process of HPV infection and can potentially be used to drive the development of therapeutics that target neutralization-sensitive sites.
External links	mBio / PubMed:28951471 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	2.042 - 9.5 Å
Structure data	EMDB-6809: The CryoEM map of HPV58 VLP in complex with the Fab fragment of antibody A12A3 Method: EM (single particle) / Resolution: 9.5 Å EMDB-6814: The CryoEM map of HPV59 VLP in complex with the Fab fragment of antibody 28F10 Method: EM (single particle) / Resolution: 8.4 Å PDB-5y9c: Crystal structure of HPV58 pentamer in complex with the Fab fragment of antibody A12A3 Method: X-RAY DIFFRACTION / Resolution: 3.443 Å PDB-5y9e: Crystal structure of HPV58 pentamer Method: X-RAY DIFFRACTION / Resolution: 2.042 Å PDB-5y9f: Crystal structure of HPV59 pentamer in complex with the Fab fragment of antibody 28F10 Method: X-RAY DIFFRACTION / Resolution: 3.35 Å
Chemicals	ChemComp-GOL: GLYCEROL ChemComp-MG: Unknown entry ChemComp-HOH: WATER
Source	human papillomavirus type 58 mus musculus (house mouse) human papillomavirus type 59
Keywords	STRUCTURAL PROTEIN/IMMUNE SYSTEM / capsid protein / STRUCTURAL PROTEIN-IMMUNE SYSTEM complex / STRUCTURAL PROTEIN / pentamer / VIRAL PROTEIN/IMMUNE SYSTEM / immune complex / VIRAL PROTEIN-IMMUNE SYSTEM complex