6p3b

Crystal structure of the anti-HIV antibody DH501 unmutated common ancestor (UCA)

spinqualitylabelsall models 6p3b, resolution 2.02Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6p3b is a 2 chain structure with sequence from Macaca mulatta. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.02Å Ligands: EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Viral glycoproteins are a primary target for host antibody responses. However, glycans on viral glycoproteins can hinder antibody recognition since they are self glycans derived from the host biosynthesis pathway. During natural HIV-1 infection, neutralizing antibodies are made against glycans on HIV-1 envelope glycoprotein (Env). However, such antibodies are rarely elicited with vaccination. Previously, the vaccine-induced, macaque antibody DH501 was isolated and shown to bind to high mannose glycans on HIV-1 Env. Understanding how DH501 underwent affinity maturation to recognize glycans could inform vaccine induction of HIV-1 glycan antibodies. Here, we show that DH501 Env glycan reactivity is mediated by both germline-encoded residues that contact glycans, and somatic mutations that increase antibody paratope flexibility. Only somatic mutations in the heavy chain were required for glycan reactivity. The paratope conformation was fragile as single mutations within the immunoglobulin fold or complementarity determining regions were sufficient for eliminating antibody function. Taken together, the initial germline VHDJH rearrangement generated contact residues capable of binding glycans, and somatic mutations were required to form a flexible paratope with a cavity conducive to HIV-1 envelope glycan binding. The requirement for the presence of most somatic mutations across the heavy chain variable region provides one explanation for the difficulty in inducing anti-Env glycan antibodies with HIV-1 Env vaccination. Cooperation between somatic mutation and germline-encoded residues enables antibody recognition of HIV-1 envelope glycans.,Wu NR, Nicely NI, Lee EM, Reed RK, Watts BE, Cai F, Walkowicz WE, Aussedat B, Jones JA, Eaton A, Trama AM, Alam SM, Montefiori DC, Haynes BF, Saunders KO PLoS Pathog. 2019 Dec 16;15(12):e1008165. doi: 10.1371/journal.ppat.1008165., eCollection 2019 Dec. PMID:31841553 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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