The Experts below are selected from a list of 9480 Experts worldwide ranked by ideXlab platform
Zihe Rao - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of severe acute respiratory syndrome coronaVirus Spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yanhui Xu, Zhiyong Lou, Hai Pang, Po Tien, George F. Gao, Yiwei Liu, Zihe RaoAbstract:Severe acute respiratory syndrome coronaVirus is a newly emergent Virus responsible for a recent outbreak of an atypical pneumonia. The coronaVirus Spike protein, an enveloped glycoprotein essential for viral entry, belongs to the class I fusion proteins and is characterized by the presence of two heptad repeat (HR) regions, HR1 and HR2. These two regions are understood to form a fusion-active conformation similar to those of other typical viral fusion proteins. This hairpin structure likely juxtaposes the viral and cellular membranes, thus facilitating membrane fusion and subsequent viral entry. The fusion core protein of severe acute respiratory syndrome coronaVirus Spike protein was crystallized, and the structure was determined at 2.8 A of resolution. The fusion core is a six-helix bundle with three HR2 helices packed against the hydrophobic grooves on the surface of central coiled coil formed by three parallel HR1 helices in an oblique antiparallel manner. This structure shares significant similarity with the fusion core structure of mouse hepatitis Virus Spike protein and other viral fusion proteins, suggesting a conserved mechanism of membrane fusion. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation, which have been successfully used in human immunodeficiency Virus 1 inhibitor development, may be applicable to the inhibition of severe acute respiratory syndrome coronaVirus on the basis of structural information provided here. The relatively deep grooves on the surface of the central coiled coil will be a good target site for the design of viral fusion inhibitors.
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structural basis for coronaVirus mediated membrane fusion crystal structure of mouse hepatitis Virus Spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yiwei Liu, Zhiyong Lou, Hai Pang, Po Tien, George F. Gao, Lan Qin, Zhihong Bai, Zihe RaoAbstract:Abstract The surface transmembrane glycoprotein is responsible for mediating virion attachment to cell and subsequent Virus-cell membrane fusion. However, the molecular mechanisms for the viral entry of coronaViruses remain poorly understood. The crystal structure of the fusion core of mouse hepatitis Virus S protein, which represents the first fusion core structure of any coronaVirus, reveals a central hydrophobic coiled coil trimer surrounded by three helices in an oblique, antiparallel manner. This structure shares significant similarity with both the low pH-induced conformation of influenza hemagglutinin and fusion core of HIV gp41, indicating that the structure represents a fusion-active state formed after several conformational changes. Our results also indicate that the mechanisms for the viral fusion of coronaViruses are similar to those of influenza Virus and HIV. The coiled coil structure has unique features, which are different from other viral fusion cores. Highly conserved heptad repeat 1 (HR1) and HR2 regions in coronaVirus Spike proteins indicate a similar three-dimensional structure among these fusion cores and common mechanisms for the viral fusion. We have proposed the binding regions of HR1 and HR2 of other coronaViruses and a structure model of their fusion core based on our mouse hepatitis Virus fusion core structure and sequence alignment. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of a number of emerging infectious diseases, including severe acute respiratory syndrome.
George F. Gao - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of severe acute respiratory syndrome coronaVirus Spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yanhui Xu, Zhiyong Lou, Hai Pang, Po Tien, George F. Gao, Yiwei Liu, Zihe RaoAbstract:Severe acute respiratory syndrome coronaVirus is a newly emergent Virus responsible for a recent outbreak of an atypical pneumonia. The coronaVirus Spike protein, an enveloped glycoprotein essential for viral entry, belongs to the class I fusion proteins and is characterized by the presence of two heptad repeat (HR) regions, HR1 and HR2. These two regions are understood to form a fusion-active conformation similar to those of other typical viral fusion proteins. This hairpin structure likely juxtaposes the viral and cellular membranes, thus facilitating membrane fusion and subsequent viral entry. The fusion core protein of severe acute respiratory syndrome coronaVirus Spike protein was crystallized, and the structure was determined at 2.8 A of resolution. The fusion core is a six-helix bundle with three HR2 helices packed against the hydrophobic grooves on the surface of central coiled coil formed by three parallel HR1 helices in an oblique antiparallel manner. This structure shares significant similarity with the fusion core structure of mouse hepatitis Virus Spike protein and other viral fusion proteins, suggesting a conserved mechanism of membrane fusion. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation, which have been successfully used in human immunodeficiency Virus 1 inhibitor development, may be applicable to the inhibition of severe acute respiratory syndrome coronaVirus on the basis of structural information provided here. The relatively deep grooves on the surface of the central coiled coil will be a good target site for the design of viral fusion inhibitors.
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structural basis for coronaVirus mediated membrane fusion crystal structure of mouse hepatitis Virus Spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yiwei Liu, Zhiyong Lou, Hai Pang, Po Tien, George F. Gao, Lan Qin, Zhihong Bai, Zihe RaoAbstract:Abstract The surface transmembrane glycoprotein is responsible for mediating virion attachment to cell and subsequent Virus-cell membrane fusion. However, the molecular mechanisms for the viral entry of coronaViruses remain poorly understood. The crystal structure of the fusion core of mouse hepatitis Virus S protein, which represents the first fusion core structure of any coronaVirus, reveals a central hydrophobic coiled coil trimer surrounded by three helices in an oblique, antiparallel manner. This structure shares significant similarity with both the low pH-induced conformation of influenza hemagglutinin and fusion core of HIV gp41, indicating that the structure represents a fusion-active state formed after several conformational changes. Our results also indicate that the mechanisms for the viral fusion of coronaViruses are similar to those of influenza Virus and HIV. The coiled coil structure has unique features, which are different from other viral fusion cores. Highly conserved heptad repeat 1 (HR1) and HR2 regions in coronaVirus Spike proteins indicate a similar three-dimensional structure among these fusion cores and common mechanisms for the viral fusion. We have proposed the binding regions of HR1 and HR2 of other coronaViruses and a structure model of their fusion core based on our mouse hepatitis Virus fusion core structure and sequence alignment. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of a number of emerging infectious diseases, including severe acute respiratory syndrome.
Ralph S Baric - One of the best experts on this subject based on the ideXlab platform.
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permissivity of dipeptidyl peptidase 4 orthologs to middle east respiratory syndrome coronaVirus is governed by glycosylation and other complex determinants
Journal of Virology, 2017Co-Authors: Kayla M Peck, Christina L Burch, Ralph S Baric, Trevor Scobey, Jesica Swanstrom, Kara Jensen, Mark T HeiseAbstract:ABSTRACT Middle East respiratory syndrome coronaVirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of Virus-receptor interactions associated with disease emergence and host susceptibility. IMPORTANCE MERS-CoV is a recently emerged zoonotic Virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However, in vivo studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the Virus Spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the Virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range.
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coronaVirus host range expansion and middle east respiratory syndrome coronaVirus emergence biochemical mechanisms and evolutionary perspectives
Annual Review of Virology, 2015Co-Authors: Kayla M Peck, Christina L Burch, Mark T Heise, Ralph S BaricAbstract:CoronaViruses have frequently expanded their host range in recent history, with two events resulting in severe disease outbreaks in human populations. Severe acute respiratory syndrome coronaVirus (SARS-CoV) emerged in 2003 in Southeast Asia and rapidly spread around the world before it was controlled by public health intervention strategies. The 2012 Middle East respiratory syndrome coronaVirus (MERS-CoV) outbreak represents another prime example of Virus emergence from a zoonotic reservoir. Here, we review the current knowledge of coronaVirus cross-species transmission, with particular focus on MERS-CoV. MERS-CoV is still circulating in the human population, and the mechanisms governing its cross-species transmission have been only partially elucidated, highlighting a need for further investigation. We discuss biochemical determinants mediating MERS-CoV host cell permissivity, including Virus Spike interactions with the MERS-CoV cell surface receptor dipeptidyl peptidase 4 (DPP4), and evolutionary mechanisms that may facilitate host range expansion, including recombination, mutator alleles, and mutational robustness. Understanding these mechanisms can help us better recognize the threat of emergence for currently circulating zoonotic strains.
Yiwei Liu - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of severe acute respiratory syndrome coronaVirus Spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yanhui Xu, Zhiyong Lou, Hai Pang, Po Tien, George F. Gao, Yiwei Liu, Zihe RaoAbstract:Severe acute respiratory syndrome coronaVirus is a newly emergent Virus responsible for a recent outbreak of an atypical pneumonia. The coronaVirus Spike protein, an enveloped glycoprotein essential for viral entry, belongs to the class I fusion proteins and is characterized by the presence of two heptad repeat (HR) regions, HR1 and HR2. These two regions are understood to form a fusion-active conformation similar to those of other typical viral fusion proteins. This hairpin structure likely juxtaposes the viral and cellular membranes, thus facilitating membrane fusion and subsequent viral entry. The fusion core protein of severe acute respiratory syndrome coronaVirus Spike protein was crystallized, and the structure was determined at 2.8 A of resolution. The fusion core is a six-helix bundle with three HR2 helices packed against the hydrophobic grooves on the surface of central coiled coil formed by three parallel HR1 helices in an oblique antiparallel manner. This structure shares significant similarity with the fusion core structure of mouse hepatitis Virus Spike protein and other viral fusion proteins, suggesting a conserved mechanism of membrane fusion. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation, which have been successfully used in human immunodeficiency Virus 1 inhibitor development, may be applicable to the inhibition of severe acute respiratory syndrome coronaVirus on the basis of structural information provided here. The relatively deep grooves on the surface of the central coiled coil will be a good target site for the design of viral fusion inhibitors.
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structural basis for coronaVirus mediated membrane fusion crystal structure of mouse hepatitis Virus Spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yiwei Liu, Zhiyong Lou, Hai Pang, Po Tien, George F. Gao, Lan Qin, Zhihong Bai, Zihe RaoAbstract:Abstract The surface transmembrane glycoprotein is responsible for mediating virion attachment to cell and subsequent Virus-cell membrane fusion. However, the molecular mechanisms for the viral entry of coronaViruses remain poorly understood. The crystal structure of the fusion core of mouse hepatitis Virus S protein, which represents the first fusion core structure of any coronaVirus, reveals a central hydrophobic coiled coil trimer surrounded by three helices in an oblique, antiparallel manner. This structure shares significant similarity with both the low pH-induced conformation of influenza hemagglutinin and fusion core of HIV gp41, indicating that the structure represents a fusion-active state formed after several conformational changes. Our results also indicate that the mechanisms for the viral fusion of coronaViruses are similar to those of influenza Virus and HIV. The coiled coil structure has unique features, which are different from other viral fusion cores. Highly conserved heptad repeat 1 (HR1) and HR2 regions in coronaVirus Spike proteins indicate a similar three-dimensional structure among these fusion cores and common mechanisms for the viral fusion. We have proposed the binding regions of HR1 and HR2 of other coronaViruses and a structure model of their fusion core based on our mouse hepatitis Virus fusion core structure and sequence alignment. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of a number of emerging infectious diseases, including severe acute respiratory syndrome.
Mark T Heise - One of the best experts on this subject based on the ideXlab platform.
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permissivity of dipeptidyl peptidase 4 orthologs to middle east respiratory syndrome coronaVirus is governed by glycosylation and other complex determinants
Journal of Virology, 2017Co-Authors: Kayla M Peck, Christina L Burch, Ralph S Baric, Trevor Scobey, Jesica Swanstrom, Kara Jensen, Mark T HeiseAbstract:ABSTRACT Middle East respiratory syndrome coronaVirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of Virus-receptor interactions associated with disease emergence and host susceptibility. IMPORTANCE MERS-CoV is a recently emerged zoonotic Virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However, in vivo studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the Virus Spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the Virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range.
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coronaVirus host range expansion and middle east respiratory syndrome coronaVirus emergence biochemical mechanisms and evolutionary perspectives
Annual Review of Virology, 2015Co-Authors: Kayla M Peck, Christina L Burch, Mark T Heise, Ralph S BaricAbstract:CoronaViruses have frequently expanded their host range in recent history, with two events resulting in severe disease outbreaks in human populations. Severe acute respiratory syndrome coronaVirus (SARS-CoV) emerged in 2003 in Southeast Asia and rapidly spread around the world before it was controlled by public health intervention strategies. The 2012 Middle East respiratory syndrome coronaVirus (MERS-CoV) outbreak represents another prime example of Virus emergence from a zoonotic reservoir. Here, we review the current knowledge of coronaVirus cross-species transmission, with particular focus on MERS-CoV. MERS-CoV is still circulating in the human population, and the mechanisms governing its cross-species transmission have been only partially elucidated, highlighting a need for further investigation. We discuss biochemical determinants mediating MERS-CoV host cell permissivity, including Virus Spike interactions with the MERS-CoV cell surface receptor dipeptidyl peptidase 4 (DPP4), and evolutionary mechanisms that may facilitate host range expansion, including recombination, mutator alleles, and mutational robustness. Understanding these mechanisms can help us better recognize the threat of emergence for currently circulating zoonotic strains.
