Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R.
Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease that caused pandemic spread in 2003. The etiological agent of SARS is a novel coronavirus (SARS-CoV). The coronaviral surface spike protein S is a type I transmembrane glycoprotein that mediates initial host binding via the cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the subsequent membrane fusion events required for cell entry. Here we report the crystal structure of the S1 receptor binding domain (RBD) in complex with a neutralizing antibody, 80R, at 2.3 A resolution, as well as the structure of the uncomplexed S1 RBD at 2.2 A resolution. We show that the 80R-binding epitope on the S1 RBD overlaps very closely with the ACE2-binding site, providing a rationale for the strong binding and broad neutralizing ability of the antibody. We provide a structural basis for the differential effects of certain mutations in the spike protein on 80R versus ACE2 binding, including escape mutants, which should facilitate the design of immunotherapeutics to treat a future SARS outbreak. We further show that the RBD of S1 forms dimers via an extensive interface that is disrupted in receptor- and antibody-bound crystal structures, and we propose a role for the dimer in virus stability and infectivity.
Hwang
William C
WC
Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Lin
Yaqiong
Y
Santelli
Eugenio
E
Sui
Jianhua
J
Jaroszewski
Lukasz
L
Stec
Boguslaw
B
Farzan
Michael
M
Marasco
Wayne A
WA
Liddington
Robert C
RC
D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D008958:Models, Molecular; D009500:Neutralization Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism*; D045169:Severe Acute Respiratory Syndrome; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*
D000914:Antibodies, Viral; D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins