Structure of the fusion core and inhibition of fusion by a heptad repeat peptide derived from the S protein of Middle East respiratory syndrome coronavirus.
Middle East respiratory syndrome coronavirus (MERS-CoV) recently emerged as a severe worldwide public health concern. The virus is highly pathogenic, manifesting in infected patients with an approximately 50% fatality rate. It is known that the surface spike (S) proteins of coronaviruses mediate receptor recognition and membrane fusion, thereby playing an indispensable role in initiating infection. In this process, heptad repeats 1 and 2 (HR1 and HR2) of the S protein assemble into a complex called the fusion core, which represents a key membrane fusion architecture. To date, however, the MERS-CoV fusion core remains uncharacterized. In this study, we performed a series of biochemical and biophysical analyses characterizing the HR1/HR2 complexes of this novel virus. The HR sequences were variably truncated and then connected with a flexible amino acid linker. In each case, the recombinant protein automatically assembled into a trimer in solution, displaying a typical α-helical structure. One of these trimers was successfully crystallized, and its structure was solved at a resolution of 1.9 Å. A canonical 6-helix bundle, like those reported for other coronaviruses, was revealed, with three HR1 helices forming the central coiled-coil core and three HR2 chains surrounding the core in the HR1 side grooves. This demonstrates that MERS-CoV utilizes a mechanism similar to those of other class I enveloped viruses for membrane fusion. With this notion, we further identified an HR2-based peptide that could potently inhibit MERS-CoV fusion and entry by using a pseudotyped-virus system. These results lay the groundwork for future inhibitory peptidic drug design.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Jing
J
Gao
Guangwen
G
Lu
Jianxun
J
Qi
Yan
Y
Li
Ying
Y
Wu
Yao
Y
Deng
Heyuan
H
Geng
Hongbin
H
Li
Qihui
Q
Wang
Haixia
H
Xiao
Wenjie
W
Tan
Jinghua
J
Yan
George F
GF
Gao
D000595:Amino Acid Sequence; D003333:Coronaviridae Infections / Q000821:virology*; D017934:Coronavirus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003460:Crystallization; D057809:HEK293 Cells; D006801:Humans; D017433:Protein Structure, Secondary; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid; D064370:Spike Glycoprotein, Coronavirus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
D064370:Spike Glycoprotein, Coronavirus