Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies
Abstract
The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP 1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 02, 2016
- Source ID
- 10.1128/mbio.02154-15
Entities
People
- Andrew I. Flyak
- Erica Ollmann Saphire
- Esther Ndungo
- James E. Crowe, Jr.
- Kartik Chandran
- Marnie L. Fusco
- Shridhar Bale
- Zachary A. Bornholdt
Organizations
- Albert Einstein College of Medicine
- Defense Threat Reduction Agency
- National Institute of Allergy and Infectious Diseases
- Scripps Research
- Vanderbilt University