Structural basis for the neutralization of MERS-CoV by a human monoclonal antibody MERS-27.
The recently reported Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness in humans with an approximately 30% mortality rate. The envelope spike glycoprotein on the surface of MERS-CoV mediates receptor binding, membrane fusion, and viral entry. We previously reported two human monoclonal antibodies that target the receptor binding domain (RBD) of the spike and exhibit strong neutralization activity against live and pesudotyped MERS-CoV infection. Here we determined the crystal structure of MERS-CoV RBD bound to the Fab fragment of MERS-27 antibody at 3.20 Å resolution. The MERS-27 epitope in the RBD overlaps with the binding site of the MERS-CoV receptor DPP4. Further biochemical, viral entry, and neutralization analyses identified two critical residues in the RBD for both MERS-27 recognition and DPP4 binding. One of the residues, Trp535, was found to function as an anchor residue at the binding interface with MERS-27. Upon receptor binding, Trp535 interacts with the N-linked carbohydrate moiety of DPP4. Thus, MERS-27 inhibits MERS-CoV infection by directly blocking both protein-protein and protein-carbohydrate interactions between MERS-CoV RBD and DPP4. These results shed light on the molecular basis of MERS-27 neutralization and will assist in the optimization of MERS-27 as a tool to combat MERS-CoV infection.
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
Xiaojuan
X
Yu
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
Senyan
S
Zhang
Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing, China.
Liwei
L
Jiang
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
Ye
Y
Cui
Beijing VDJBio Co., Ltd, Suite B311, 5 Kaituo Road, Zhongguancun BioMedical Garden, Haidian District, Beijing, China.
Dongxia
D
Li
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
Dongli
D
Wang
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
Nianshuang
N
Wang
Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing, China.
Lili
L
Fu
Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing, China.
Xuanlin
X
Shi
Beijing VDJBio Co., Ltd, Suite B311, 5 Kaituo Road, Zhongguancun BioMedical Garden, Haidian District, Beijing, China.
Ziqiang
Z
Li
Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing, China.
Linqi
L
Zhang
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.|Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Xinquan
X
Wang
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000648:ultrastructure*; D000998:Antiviral Agents / Q000737:chemistry; D001665:Binding Sites; D006801:Humans; D065207:Middle East Respiratory Syndrome Coronavirus / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000648:ultrastructure*
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D014759:Viral Envelope Proteins