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oai:figshare.com:article/34048939 2026-10-01T17:40:25Z category_1 category_8 category_24 category_39 category_46 category_734 category_128 category_132 category_134 portal_5 item_type_1 month_year_10_2026

<p>VA14_26 and V1WT_41 bind epitopes that overlap with the RBD class 4 epitope.</p> Ayush Upadhyay (25157573) Jeffrey Seow (9415776) Yilmaz Alguel (24840073) Joseph Newman (5638340) Nazia Thakur (9904162) Abigail L. Hay (25157576) Jerry C. H. Tam (13955938) Andrea Nans (5176226) Richard J. Orton (7832015) Dalan Bailey (193037) Peter Cherepanov (369) Katie J. Doores (346210) Biophysics Microbiology Evolutionary Biology Ecology Immunology Biological Sciences not elsewhere classified Hematology Infectious Diseases Virology v1wt_06 contact residues therapeutic antibody development reactive monoclonal antibodies mab v1wt_06 binds increasing spillover potential human population presents heavy chain alone future therapeutic use confer broad sarbecovirus circulating viruses suggesting 2 variant neutralisation 2 variants xlink "> virus entry urgent need rationale design rational design neutralising epitopes including xec ideal candidates highly conserved functionally constrained discover cross differing angles continuing evolution ace2 competition <p><b>A)</b> VA14_26 and V1WT_41 antibody footprints overlayed with the epitope footprints of other RBD class 4 neutralising antibodies including CR3022, 10−40, ADI-62113 [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref037" target="_blank">37</a>–<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref039" target="_blank">39</a>]. SARS-CoV-2 RBD (from PDB: 6m0j) is coloured based on the amino acid conservation across 87 bat sarbecoviruses [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref006" target="_blank">6</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref023" target="_blank">23</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref081" target="_blank">81</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref082" target="_blank">82</a>]. <b>B)</b> Superimposed 3D structure depicting the binding of VA14_26 (Red) to WIV-1 RBD (blue) in relation to ACE2 (orange, from PDB: 8WLZ) and CR3022 (pink, from PDB: 6W41). <b>C)</b> Superimposed 3D structure depicting the binding of V1WT_41 (green) to WIV-1 RBD (blue) in relation to ACE2 (orange, from PDB: 8WLZ). <b>D)</b> Sequence alignment of a panel of bat sarbecovirus RBDs. Contact residues for VA14_26 and V1WT_41 are indicated by red and pink dots and outline, respectively. Shared contact residues are shown with yellow dots and outline. <b>E)</b> Sequence alignment of a panel of SARS-CoV-2 variant RBDs. Contact residues for VA14_26 and V1WT_41 are indicated by red and pink dots and outline, respectively. Shared contact residues are shown with yellow dots and outline. The colouring scheme describes the percent identity (PID) between the sequences as implemented in Jalview 2.11.4.0. <b>F)</b> A close-up view of YYDRSG motif in V1WT_41 HCDR3 (green) in contact with WIV-1 RBD (grey), shown in stick representation, renumbered based on alignment to SARS-CoV-2 [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref038" target="_blank">38</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref039" target="_blank">39</a>]. Presence of G109 breaks the H-bonding pattern in the beta hairpin to create a G1 β-bulge. This further enables D106 side chain to make hydrogen bond with the amides in the protein backbone, thereby stabilising the local structure. Combined this accentuates a right-handed twist found in G1 β-bulge [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref083" target="_blank">83</a>]. Twisting of the β-hairpin is thought to contribute towards stabilisation of RBD-Fab interaction in several other public mAbs with YYDRxG motif [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref038" target="_blank">38</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.3003882#pbio.3003882.ref039" target="_blank">39</a>].</p> 2026-10-01T17:40:02Z Image Figure 10.1371/journal.pbio.3003882.g003 https://figshare.com/articles/figure/_p_VA14_26_and_V1WT_41_bind_epitopes_that_overlap_with_the_RBD_class_4_epitope_p_/34048939 CC BY 4.0