Receptor recognition by viruses is the first and essential step of viral infections. It is an important determinant of viral host ranges and cross-species infections, and a primary target for human intervention. Coronaviruses recognize a variety of receptors, infect many hosts, and are significant health threats to humans and other animals. NL63 coronavirus (NL63-CoV), a prevalent human respiratory virus, is the only group-I coronavirus known to use angiotensin-converting enzyme 2 (ACE2) as its receptor, whereas other group-I coronaviruses use aminopeptidase-N (APN). Curiously, ACE2 is also used by group-II SARS coronavirus (SARS-CoV), the agent for the fatal human severe acute respiratory syndrome (SARS). Defined receptor-binding domains (RBDs) on the spike proteins of NL63-CoV and SARS-CoV bind ACE2 with high affinity. This research investigates the receptor recognition mechanisms and cross-species infections of coronaviruses. Our preliminary studies have determined the crystal structures of NL63-CoV RBD complexed with human ACE2 and of SARS-CoV RBD complexed with human ACE2. NL63-CoV and SARS-CoV RBDs have no structural homology in cores or receptor-binding motifs (RBMs) that directly contact ACE2, but recognize the same "virus-binding hotspot" on ACE2. Among group-I coronaviruses, RBD cores are conserved, but RBMs are variable, explaining how these viruses recognize different receptors. We have also determined crystal structures of the RBDs from various SARS-CoV strains complexed with ACE2 proteins from humans and palm civets, revealing mechanisms whereby SARS-CoV transmitted between the two hosts. There are three specific aims in this project.
Aim 1 focuses on the receptor recognition mechanisms of group-I NL63-CoV. It investigates specific functions of the virus-binding hotspot on human ACE2 in NL63-CoV binding, and examines interactions between the NL63-CoV spike protein and ACE2 proteins from non-human hosts.
Aim 2 focuses on the receptor recognition mechanisms of other group-I coronaviruses. It investigates specific functions of the RBMs of other group-I coronavirus spike proteins, and studies whether modifying the RBMs changes the receptor specificities of the spike proteins.
Aim 3 focuses on the receptor recognition mechanisms of group-II SARS-CoV. It investigates why mutations in the RBM region of past SARS-CoV strains were selected, whether and how these mutations affect receptor binding, and what combinations of these mutations may appear in potential future SARS-CoV strains. The research approaches of this proposal include crystallographic analysis of the virus-receptor interfaces, identification of structural elements important for virus-receptor interactions, and characterization of these elements using crystallographic, biochemical, molecular, and virological tools. Overall, these studies will provide the molecular and structural basis for understanding viral evolution, virus-receptor interactions, viral host ranges and cross-species infections. They will also guide the development of novel antiviral strategies against coronavirus infections.
This research investigates how coronaviruses recognize their receptors and how they interact with receptors from different hosts. It explores novel principles governing viral evolution, virus-receptor interactions, viral host ranges and cross-species infections, and may lead to new approaches in the prevention and treatment of coronavirus infections in humans and other animals.
|Liu, Chang; Ma, Yuanmei; Yang, Yang et al. (2016) Cell Entry of Porcine Epidemic Diarrhea Coronavirus Is Activated by Lysosomal Proteases. J Biol Chem 291:24779-24786|
|Yang, Yang; Liu, Chang; Du, Lanying et al. (2015) Two Mutations Were Critical for Bat-to-Human Transmission of Middle East Respiratory Syndrome Coronavirus. J Virol 89:9119-23|
|Li, Fang (2015) Receptor recognition mechanisms of coronaviruses: a decade of structural studies. J Virol 89:1954-64|
|Liu, Chang; Tang, Jian; Ma, Yuanmei et al. (2015) Receptor usage and cell entry of porcine epidemic diarrhea coronavirus. J Virol 89:6121-5|
|Du, Lanying; Zhao, Guangyu; Yang, Yang et al. (2014) A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein. J Virol 88:7045-53|
|Ma, Cuiqing; Wang, Lili; Tao, Xinrong et al. (2014) Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design. Vaccine 32:6170-6|
|Yang, Yang; Du, Lanying; Liu, Chang et al. (2014) Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc Natl Acad Sci U S A 111:12516-21|
|Li, Fang (2013) Receptor recognition and cross-species infections of SARS coronavirus. Antiviral Res 100:246-54|
|Rastogi, Rachna; Teller, Ryan S; Mesquita, Pedro M M et al. (2013) Osmotic pump tablets for delivery of antiretrovirals to the vaginal mucosa. Antiviral Res 100:255-8|
|Chen, Yaoqing; Rajashankar, Kanagalaghatta R; Yang, Yang et al. (2013) Crystal structure of the receptor-binding domain from newly emerged Middle East respiratory syndrome coronavirus. J Virol 87:10777-83|
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