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PDBsum entry 4hs8
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Immune system
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PDB id
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4hs8
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Contents |
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12 a.a.
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225 a.a.
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218 a.a.
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PDB id:
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| Name: |
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Immune system
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Title:
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Hepatitus c envelope glycoprotein e2 fragment 412-423 with humanized and affinity-matured antibody hu5b3.V3
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Structure:
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E2-peptide. Chain: a. Fragment: unp residues 50-62. Engineered: yes. Antibody hu5b3.V2 fab heavy chain. Chain: h. Engineered: yes. Antibody hu5b3.V2 fab light chain. Chain: l.
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Source:
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Synthetic: yes. Hepatitis c virus. Organism_taxid: 11103. Other_details: this sequence occurs naturally in hepatitus c virus. Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.60Å
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R-factor:
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0.225
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R-free:
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0.264
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Authors:
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C.Eigenbrot,M.Ultsch
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Key ref:
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H.Pantua
et al.
(2013).
Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies.
J Mol Biol,
425,
1899-1914.
PubMed id:
DOI:
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Date:
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29-Oct-12
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Release date:
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03-Apr-13
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PROCHECK
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Headers
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References
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Q9YK84
(Q9YK84_9HEPC) -
Genome polyprotein (Fragment) from Hepacivirus hominis
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Seq:
Struc:
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135 a.a.
12 a.a.
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DOI no:
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J Mol Biol
425:1899-1914
(2013)
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PubMed id:
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Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies.
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H.Pantua,
J.Diao,
M.Ultsch,
M.Hazen,
M.Mathieu,
K.McCutcheon,
K.Takeda,
S.Date,
T.K.Cheung,
Q.Phung,
P.Hass,
D.Arnott,
J.A.Hongo,
D.J.Matthews,
A.Brown,
A.H.Patel,
R.F.Kelley,
C.Eigenbrot,
S.B.Kapadia.
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ABSTRACT
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Hepatitis C virus (HCV) infection is a major cause of liver disease and
hepatocellular carcinoma. Glycan shielding has been proposed to be a mechanism
by which HCV masks broadly neutralizing epitopes on its viral glycoproteins.
However, the role of altered glycosylation in HCV resistance to broadly
neutralizing antibodies is not fully understood. Here, we have generated potent
HCV neutralizing antibodies hu5B3.v3 and MRCT10.v362 that, similar to the
previously described AP33 and HCV1, bind to a highly conserved linear epitope on
E2. We utilize a combination of in vitro resistance selections using the cell
culture infectious HCV and structural analyses to identify mechanisms of HCV
resistance to hu5B3.v3 and MRCT10.v362. Ultra deep sequencing from in vitro HCV
resistance selection studies identified resistance mutations at asparagine N417
(N417S, N417T and N417G) as early as 5days post treatment. Comparison of the
glycosylation status of soluble versions of the E2 glycoprotein containing the
respective resistance mutations revealed a glycosylation shift from N417 to N415
in the N417S and N417T E2 proteins. The N417G E2 variant was glycosylated
neither at residue 415 nor at residue 417 and remained sensitive to MRCT10.v362.
Structural analyses of the E2 epitope bound to hu5B3.v3 Fab and MRCT10.v362 Fab
using X-ray crystallography confirmed that residue N415 is buried within the
antibody-peptide interface. Thus, in addition to previously described mutations
at N415 that abrogate the β-hairpin structure of this E2 linear epitope, we
identify a second escape mechanism, termed glycan shifting, that decreases the
efficacy of broadly neutralizing HCV antibodies.
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Links
