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Article ; Online: Leveraging Fungal and Human Calcineurin-Inhibitor Structures, Biophysical Data, and Dynamics To Design Selective and Nonimmunosuppressive FK506 Analogs.

Gobeil, Sophie M-C / Bobay, Benjamin G / Juvvadi, Praveen R / Cole, D Christopher / Heitman, Joseph / Steinbach, William J / Venters, Ronald A / Spicer, Leonard D

mBio

2021 Volume 12, Issue 6, Page(s) e0300021

Abstract: Calcineurin is a critical enzyme in fungal pathogenesis and antifungal drug tolerance and, therefore, an attractive antifungal target. Current clinically accessible calcineurin inhibitors, such as FK506, are immunosuppressive to humans, so exploiting ... ...

Abstract	Calcineurin is a critical enzyme in fungal pathogenesis and antifungal drug tolerance and, therefore, an attractive antifungal target. Current clinically accessible calcineurin inhibitors, such as FK506, are immunosuppressive to humans, so exploiting calcineurin inhibition as an antifungal strategy necessitates fungal specificity in order to avoid inhibiting the human pathway. Harnessing fungal calcineurin-inhibitor crystal structures, we recently developed a less immunosuppressive FK506 analog, APX879, with broad-spectrum antifungal activity and demonstrable efficacy in a murine model of invasive fungal infection. Our overarching goal is to better understand, at a molecular level, the interaction determinants of the human and fungal FK506-binding proteins (FKBP12) required for calcineurin inhibition in order to guide the design of fungus-selective, nonimmunosuppressive FK506 analogs. To this end, we characterized high-resolution structures of the Mucor circinelloides FKBP12 bound to FK506 and of the Aspergillus fumigatus,
MeSH term(s)	Amino Acid Sequence ; Antifungal Agents/chemistry ; Antifungal Agents/pharmacology ; Calcineurin/chemistry ; Calcineurin/genetics ; Calcineurin/metabolism ; Calcineurin Inhibitors/chemistry ; Calcineurin Inhibitors/pharmacology ; Drug Design ; Fungal Proteins/chemistry ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Host-Pathogen Interactions ; Humans ; Mucor/drug effects ; Mucor/genetics ; Mucor/metabolism ; Mucormycosis/drug therapy ; Mucormycosis/genetics ; Mucormycosis/metabolism ; Mucormycosis/microbiology ; Sequence Alignment ; Tacrolimus/chemistry ; Tacrolimus/pharmacology ; Tacrolimus Binding Protein 1A/chemistry ; Tacrolimus Binding Protein 1A/genetics ; Tacrolimus Binding Protein 1A/metabolism
Chemical Substances	Antifungal Agents ; Calcineurin Inhibitors ; Fungal Proteins ; Calcineurin (EC 3.1.3.16) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2021-11-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.03000-21
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Article ; Online: 15

Gobeil, Sophie M C / Bobay, Benjamin G / Spicer, Leonard D / Venters, Ronald A

Biomolecular NMR assignments

2019 Volume 13, Issue 1, Page(s) 207–212

Abstract: Invasive fungal infections are a leading cause of death in immunocompromised patients and remain difficult to treat since fungal pathogens, like mammals, are eukaryotes and share many orthologous proteins. As a result, current antifungal drugs have ... ...

Abstract	Invasive fungal infections are a leading cause of death in immunocompromised patients and remain difficult to treat since fungal pathogens, like mammals, are eukaryotes and share many orthologous proteins. As a result, current antifungal drugs have limited clinical value, are sometimes toxic, can adversely affect human reaction pathways and are increasingly ineffective due to emerging resistance. One potential antifungal drug, FK506, establishes a ternary complex between the phosphatase, calcineurin, and the 12-kDa peptidyl-prolyl isomerase FK506-binding protein, FKBP12. It has been well established that calcineurin, highly conserved from yeast to mammals, is necessary for invasive fungal disease and is inhibited when in complex with FK506/FKBP12. Unfortunately, FK506 is also immunosuppressive in humans, precluding its usage as an antifungal drug, especially in immunocompromised patients. Whereas the homology between human and fungal calcineurin proteins is > 80%, the human and fungal FKBP12s share 48-58% sequence identity, making them more amenable candidates for drug targeting efforts. Here we report the backbone and sidechain NMR assignments of recombinant FKBP12 proteins from the pathogenic fungi Mucor circinelloides and Aspergillus fumigatus in the apo form and compare these to the backbone assignments of the FK506 bound form. In addition, we report the backbone assignments of the apo and FK506 bound forms of the Homo sapiens FKBP12 protein for evaluation against the fungal forms. These data are the first steps towards defining, at a residue specific level, the impacts of FK506 binding to fungal and mammalian FKBP12 proteins. Our data highlight differences between the human and fungal FKBP12s that could lead to the design of more selective anti-fungal drugs.
MeSH term(s)	Amino Acid Sequence ; Aspergillus fumigatus/chemistry ; Carbon Isotopes ; Fungal Proteins/chemistry ; Mucor/chemistry ; Nitrogen Isotopes ; Nuclear Magnetic Resonance, Biomolecular ; Proteins ; Tacrolimus Binding Protein 1A/chemistry
Chemical Substances	Carbon Isotopes ; Fungal Proteins ; Nitrogen Isotopes ; Nitrogen-15 ; Proteins ; Tacrolimus Binding Protein 1A (EC 5.2.1.-) ; Carbon-13 (FDJ0A8596D)
Language	English
Publishing date	2019-02-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2388861-1
ISSN	1874-270X ; 1874-2718
ISSN (online)	1874-270X
ISSN	1874-2718
DOI	10.1007/s12104-019-09878-x
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Article ; Online: FKBP12 dimerization mutations effect FK506 binding and differentially alter calcineurin inhibition in the human pathogen Aspergillus fumigatus.

Juvvadi, Praveen R / Bobay, Benjamin G / Gobeil, Sophie M C / Cole, D Christopher / Venters, Ronald A / Heitman, Joseph / Spicer, Leonard D / Steinbach, William J

Biochemical and biophysical research communications

2020 Volume 526, Issue 1, Page(s) 48–54

Abstract: The 12-kDa FK506-binding protein (FKBP12) is the target of the commonly used immunosuppressive drug FK506. The FKBP12-FK506 complex binds to calcineurin and inhibits its activity, leading to immunosuppression and preventing organ transplant rejection. ... ...

Abstract	The 12-kDa FK506-binding protein (FKBP12) is the target of the commonly used immunosuppressive drug FK506. The FKBP12-FK506 complex binds to calcineurin and inhibits its activity, leading to immunosuppression and preventing organ transplant rejection. Our recent characterization of crystal structures of FKBP12 proteins in pathogenic fungi revealed the involvement of the 80's loop residue (Pro90) in the active site pocket in self-substrate interaction providing novel evidence on FKBP12 dimerization in vivo. The 40's loop residues have also been shown to be involved in reversible dimerization of FKBP12 in the mammalian and yeast systems. To understand how FKBP12 dimerization affects FK506 binding and influences calcineurin function, we generated Aspergillus fumigatus FKBP12 mutations in the 40's and 50's loop (F37 M/L; W60V). Interestingly, the mutants exhibited variable FK506 susceptibility in vivo indicating differing dimer strengths. In comparison to the 80's loop P90G and V91C mutants, the F37 M/L and W60V mutants exhibited greater FK506 resistance, with the F37M mutation showing complete loss in calcineurin binding in vivo. Molecular dynamics and pulling simulations for each dimeric FKBP12 protein revealed a two-fold increase in dimer strength and significantly higher number of contacts for the F37M, F37L, and W60V mutations, further confirming their varying degree of impact on FK506 binding and calcineurin inhibition in vivo.
MeSH term(s)	Amino Acid Sequence ; Aspergillus fumigatus/metabolism ; Calcineurin/metabolism ; Calcineurin Inhibitors/pharmacology ; Computer Simulation ; Fungal Proteins/chemistry ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Humans ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Mutation/genetics ; Protein Binding/drug effects ; Protein Multimerization ; Protein Structure, Secondary ; Tacrolimus/pharmacology ; Tacrolimus Binding Protein 1A/chemistry ; Tacrolimus Binding Protein 1A/genetics ; Tacrolimus Binding Protein 1A/metabolism
Chemical Substances	Calcineurin Inhibitors ; Fungal Proteins ; Mutant Proteins ; Calcineurin (EC 3.1.3.16) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2020-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2020.03.062
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Article: FKBP12 dimerization mutations effect FK506 binding and differentially alter calcineurin inhibition in the human pathogen Aspergillus fumigatus

Juvvadi, Praveen R / Bobay, Benjamin G / Gobeil, Sophie M.C / Cole, D. Christopher / Venters, Ronald A / Heitman, Joseph / Spicer, Leonard D / Steinbach, William J

Biochemical and biophysical research communications. 2020 May 21, v. 526, no. 1

2020

Abstract	The 12-kDa FK506-binding protein (FKBP12) is the target of the commonly used immunosuppressive drug FK506. The FKBP12-FK506 complex binds to calcineurin and inhibits its activity, leading to immunosuppression and preventing organ transplant rejection. Our recent characterization of crystal structures of FKBP12 proteins in pathogenic fungi revealed the involvement of the 80’s loop residue (Pro90) in the active site pocket in self-substrate interaction providing novel evidence on FKBP12 dimerization in vivo. The 40’s loop residues have also been shown to be involved in reversible dimerization of FKBP12 in the mammalian and yeast systems. To understand how FKBP12 dimerization affects FK506 binding and influences calcineurin function, we generated Aspergillus fumigatus FKBP12 mutations in the 40’s and 50’s loop (F37 M/L; W60V). Interestingly, the mutants exhibited variable FK506 susceptibility in vivo indicating differing dimer strengths. In comparison to the 80’s loop P90G and V91C mutants, the F37 M/L and W60V mutants exhibited greater FK506 resistance, with the F37M mutation showing complete loss in calcineurin binding in vivo. Molecular dynamics and pulling simulations for each dimeric FKBP12 protein revealed a two-fold increase in dimer strength and significantly higher number of contacts for the F37M, F37L, and W60V mutations, further confirming their varying degree of impact on FK506 binding and calcineurin inhibition in vivo.
Keywords	Aspergillus fumigatus ; active sites ; animal pathogens ; dimerization ; drugs ; graft rejection ; immunosuppression ; mammals ; molecular dynamics ; mutation ; organ transplantation ; research ; yeasts
Language	English
Dates of publication	2020-0521
Size	p. 48-54.
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2020.03.062
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Article ; Online: 15N, 13C and 1H backbone resonance assignments of an artificially engineered TEM-1/PSE-4 class A β-lactamase chimera and its deconvoluted mutant.

Gobeil, Sophie M C / Gagné, Donald / Doucet, Nicolas / Pelletier, Joelle N

Biomolecular NMR assignments

2016 Volume 10, Issue 1, Page(s) 93–99

Abstract: The widespread use of β-lactam antibiotics has given rise to a dramatic increase in clinically-relevant β-lactamases. Understanding the structure/function relation in these variants is essential to better address the ever-growing incidence of antibiotic ... ...

Abstract	The widespread use of β-lactam antibiotics has given rise to a dramatic increase in clinically-relevant β-lactamases. Understanding the structure/function relation in these variants is essential to better address the ever-growing incidence of antibiotic resistance. We previously reported the backbone resonance assignments of a chimeric protein constituted of segments of the class A β-lactamases TEM-1 and PSE-4 (Morin et al. in Biomol NMR Assign 4:127-130, 2010. doi: 10.1007/s12104-010-9227-8 ). That chimera, cTEM17m, held 17 amino acid substitutions relative to TEM-1 β-lactamase, resulting in a well-folded and fully functional protein with increased dynamics. Here we report the (1)H, (13)C and (15)N backbone resonance assignments of chimera cTEM-19m, which includes 19 substitutions and exhibits increased active-site perturbation, as well as one of its deconvoluted variants, as the first step in the analysis of their dynamic behaviours.
MeSH term(s)	Carbon Isotopes ; Mutant Proteins/chemistry ; Nitrogen Isotopes ; Nuclear Magnetic Resonance, Biomolecular ; Protein Engineering ; Protein Structure, Secondary ; Recombinant Proteins/chemistry ; Tritium ; beta-Lactamases/chemistry
Chemical Substances	Carbon Isotopes ; Mutant Proteins ; Nitrogen Isotopes ; Recombinant Proteins ; Tritium (10028-17-8) ; beta-lactamase PSE-1 (EC 3.5.2.-) ; beta-Lactamases (EC 3.5.2.6) ; beta-lactamase TEM-1 (EC 3.5.2.6)
Language	English
Publishing date	2016-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2388861-1
ISSN	1874-270X ; 1874-2718
ISSN (online)	1874-270X
ISSN	1874-2718
DOI	10.1007/s12104-015-9645-8
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Article: Effect of natural mutations of SARS-CoV-2 on spike structure, conformation and antigenicity.

Gobeil, Sophie M-C / Janowska, Katarzyna / McDowell, Shana / Mansouri, Katayoun / Parks, Robert / Stalls, Victoria / Kopp, Megan F / Manne, Kartik / Saunders, Kevin / Edwards, Robert J / Haynes, Barton F / Henderson, Rory C / Acharya, Priyamvada

bioRxiv : the preprint server for biology

2021

Abstract: New SARS-CoV-2 variants that have accumulated multiple mutations in the spike (S) glycoprotein enable increased transmission and resistance to neutralizing antibodies. Here, we study the antigenic and structural impacts of the S protein mutations from ... ...

Abstract	New SARS-CoV-2 variants that have accumulated multiple mutations in the spike (S) glycoprotein enable increased transmission and resistance to neutralizing antibodies. Here, we study the antigenic and structural impacts of the S protein mutations from four variants, one that was involved in transmission between minks and humans, and three that rapidly spread in human populations and originated in the United Kingdom, Brazil or South Africa. All variants either retained or improved binding to the ACE2 receptor. The B.1.1.7 (UK) and B.1.1.28 (Brazil) spike variants showed reduced binding to neutralizing NTD and RBD antibodies, respectively, while the B.1.351 (SA) variant showed reduced binding to both NTD- and RBD-directed antibodies. Cryo-EM structural analyses revealed allosteric effects of the mutations on spike conformations and revealed mechanistic differences that either drive inter-species transmission or promotes viral escape from dominant neutralizing epitopes. Highlights: Cryo-EM structures reveal changes in SARS-CoV-2 S protein during inter-species transmission or immune evasion.Adaptation to mink resulted in increased ACE2 binding and spike destabilization.B.1.1.7 S mutations reveal an intricate balance of stabilizing and destabilizing effects that impact receptor and antibody binding.E484K mutation in B.1.351 and B.1.1.28 S proteins drives immune evasion by altering RBD conformation.S protein uses different mechanisms to converge upon similar solutions for altering RBD up/down positioning.
Language	English
Publishing date	2021-03-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.11.435037
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Article ; Online: The Structural Dynamics of Engineered β-Lactamases Vary Broadly on Three Timescales yet Sustain Native Function.

Gobeil, Sophie M C / Ebert, Maximillian C C J C / Park, Jaeok / Gagné, Donald / Doucet, Nicolas / Berghuis, Albert M / Pleiss, Jürgen / Pelletier, Joelle N

Scientific reports

2019 Volume 9, Issue 1, Page(s) 6656

Abstract: Understanding the principles of protein dynamics will help guide engineering of protein function: altering protein motions may be a barrier to success or may be an enabling tool for protein engineering. The impact of dynamics on protein function is ... ...

Abstract	Understanding the principles of protein dynamics will help guide engineering of protein function: altering protein motions may be a barrier to success or may be an enabling tool for protein engineering. The impact of dynamics on protein function is typically reported over a fraction of the full scope of motional timescales. If motional patterns vary significantly at different timescales, then only by monitoring motions broadly will we understand the impact of protein dynamics on engineering functional proteins. Using an integrative approach combining experimental and in silico methodologies, we elucidate protein dynamics over the entire span of fast to slow timescales (ps to ms) for a laboratory-engineered system composed of five interrelated β-lactamases: two natural homologs and three laboratory-recombined variants. Fast (ps-ns) and intermediate (ns-µs) dynamics were mostly conserved. However, slow motions (µs-ms) were few and conserved in the natural homologs yet were numerous and widely dispersed in their recombinants. Nonetheless, modified slow dynamics were functionally tolerated. Crystallographic B-factors from high-resolution X-ray structures were partly predictive of the conserved motions but not of the new slow motions captured in our solution studies. Our inspection of protein dynamics over a continuous range of timescales vividly illustrates the complexity of dynamic impacts of protein engineering as well as the functional tolerance of an engineered enzyme system to new slow motions.
MeSH term(s)	Binding Sites ; Crystallography, X-Ray ; Kinetics ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation ; Protein Engineering ; beta-Lactamases/chemistry ; beta-Lactamases/metabolism
Chemical Substances	beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2019-04-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-42866-8
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Article ; Online: Development of sulfahydantoin derivatives as β-lactamase inhibitors.

Paquet-Côté, Pierre-Alexandre / Alejaldre, Lorea / Lapointe Verreault, Camille / Gobeil, Sophie M C / Lamoureux, Rosalie / Bédard, Laurie / Normandeau, Charles-Olivier / Lemay-St-Denis, Claudèle / Pelletier, Joelle N / Voyer, Normand

Bioorganic & medicinal chemistry letters

2021 Volume 35, Page(s) 127781

Abstract: Sulfahydantoin-based molecules may provide a means to counteract antibiotic resistance, which is on the rise. These molecules may act as inhibitors of β-lactamase enzymes, which are key in some resistance mechanisms. In this paper, we report on the ... ...

Abstract	Sulfahydantoin-based molecules may provide a means to counteract antibiotic resistance, which is on the rise. These molecules may act as inhibitors of β-lactamase enzymes, which are key in some resistance mechanisms. In this paper, we report on the synthesis of 6 novel sulfahydantoin derivatives by the key reaction of chlorosulfonyl isocyanate to form α-amino acid derived sulfamides, and their cyclization into sulfahydantoins. The synthesis is rapid and provides the target compounds in 8 steps. We investigated their potential as β-lactamase inhibitors using two common Class A β-lactamases, TEM-1 and the prevalent extended-spectrum TEM-15. Two compounds, 3 and 6, show substantial inhibition of the β-lactamases with IC
MeSH term(s)	Dose-Response Relationship, Drug ; Drug Development ; Humans ; Molecular Structure ; Structure-Activity Relationship ; Sulfur Compounds/chemical synthesis ; Sulfur Compounds/chemistry ; Sulfur Compounds/pharmacology ; beta-Lactamase Inhibitors/chemical synthesis ; beta-Lactamase Inhibitors/chemistry ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactamases/metabolism
Chemical Substances	Sulfur Compounds ; beta-Lactamase Inhibitors ; beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2021-01-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2021.127781
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Article: Structural diversity of the SARS-CoV-2 Omicron spike

Gobeil, Sophie M.-C. / Henderson, Rory / Stalls, Victoria / Janowska, Katarzyna / Huang, Xiao / May, Aaron / Speakman, Micah / Beaudoin, Esther / Manne, Kartik / Li, Dapeng / Parks, Rob / Barr, Maggie / Deyton, Margaret / Martin, Mitchell / Mansouri, Katayoun / Edwards, Robert J. / Eaton, Amanda / Montefiori, David C. / Sempowski, Gregory D. /

Saunders, Kevin O. / Wiehe, Kevin / Williams, Wilton / Korber, Bette / Haynes, Barton F. / Acharya, Priyamvada

Molecular cell. 2022 Mar. 21,

2022

Abstract: Aided by extensive spike protein mutation, the SARS-CoV-2 Omicron variant overtook the previously dominant Delta variant. Spike conformation plays an essential role in SARS-CoV-2 evolution via changes in receptor-binding domain (RBD) and neutralizing ... ...

Abstract	Aided by extensive spike protein mutation, the SARS-CoV-2 Omicron variant overtook the previously dominant Delta variant. Spike conformation plays an essential role in SARS-CoV-2 evolution via changes in receptor-binding domain (RBD) and neutralizing antibody epitope presentation, affecting virus transmissibility and immune evasion. Here, we determine cryo-EM structures of the Omicron and Delta spikes to understand the conformational impacts of mutations in each. The Omicron spike structure revealed an unusually tightly packed RBD organization with long range impacts that were not observed in the Delta spike. Binding and crystallography revealed increased flexibility at the functionally critical fusion peptide site in the Omicron spike. These results reveal a highly evolved Omicron spike architecture with possible impacts on its high levels of immune evasion and transmissibility.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; crystallography ; epitopes ; immune evasion ; mutation ; peptides ; viruses
Language	English
Dates of publication	2022-0321
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.03.028
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Article ; Online: D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction.

Gobeil, Sophie M-C / Janowska, Katarzyna / McDowell, Shana / Mansouri, Katayoun / Parks, Robert / Manne, Kartik / Stalls, Victoria / Kopp, Megan F / Henderson, Rory / Edwards, Robert J / Haynes, Barton F / Acharya, Priyamvada

Cell reports

2020 Volume 34, Issue 2, Page(s) 108630

Abstract: The severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein ... ...

Abstract	The severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic and are now the dominant form worldwide. Here, we explore S conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryoelectron microscopy (cryo-EM) structures reveal altered receptor binding domain (RBD) disposition; antigenicity and proteolysis experiments reveal structural changes and enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the up/down ratio of the RBDs in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, which harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 S conformational landscape and allostery and have implications for vaccine design.
MeSH term(s)	COVID-19/pathology ; COVID-19/virology ; Cryoelectron Microscopy ; Humans ; Immunogenicity, Vaccine ; Molecular Dynamics Simulation ; Mutation ; Peptide Hydrolases/metabolism ; Protein Domains ; Protein Stability ; Protein Structure, Quaternary ; Protein Subunits/metabolism ; Proteolysis ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Protein Subunits ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2020-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.108630
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