4JY4

Crystal structure of human Fab PGT121, a broadly reactive and potent HIV-1 neutralizing antibody

4JY4 の概要

• エントリーDOI: 10.2210/pdb4jy4/pdb
• 関連するPDBエントリー: 4JY5 4JY6
• 分子名称: PGT121 heavy chain, PGT121 light chain, N-acetyl-alpha-neuraminic acid-(2-6)-beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: broadly neutralizing antibody against hiv-1, hiv-1 env gp120 subunit, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49734.01

構造登録者

Julien, J.-P.,Diwanji, D.C.,Burton, D.R.,Wilson, I.A. (登録日: 2013-03-29, 公開日: 2013-05-15, 最終更新日: 2024-11-20)

主引用文献

Julien, J.P.,Sok, D.,Khayat, R.,Lee, J.H.,Doores, K.J.,Walker, L.M.,Ramos, A.,Diwanji, D.C.,Pejchal, R.,Cupo, A.,Katpally, U.,Depetris, R.S.,Stanfield, R.L.,McBride, R.,Marozsan, A.J.,Paulson, J.C.,Sanders, R.W.,Moore, J.P.,Burton, D.R.,Poignard, P.,Ward, A.B.,Wilson, I.A.
Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans.
Plos Pathog., 9:e1003342-e1003342, 2013

PubMed Abstract: New broad and potent neutralizing HIV-1 antibodies have recently been described that are largely dependent on the gp120 N332 glycan for Env recognition. Members of the PGT121 family of antibodies, isolated from an African donor, neutralize ∼70% of circulating isolates with a median IC50 less than 0.05 µg ml(-1). Here, we show that three family members, PGT121, PGT122 and PGT123, have very similar crystal structures. A long 24-residue HCDR3 divides the antibody binding site into two functional surfaces, consisting of an open face, formed by the heavy chain CDRs, and an elongated face, formed by LCDR1, LCDR3 and the tip of the HCDR3. Alanine scanning mutagenesis of the antibody paratope reveals a crucial role in neutralization for residues on the elongated face, whereas the open face, which accommodates a complex biantennary glycan in the PGT121 structure, appears to play a more secondary role. Negative-stain EM reconstructions of an engineered recombinant Env gp140 trimer (SOSIP.664) reveal that PGT122 interacts with the gp120 outer domain at a more vertical angle with respect to the top surface of the spike than the previously characterized antibody PGT128, which is also dependent on the N332 glycan. We then used ITC and FACS to demonstrate that the PGT121 antibodies inhibit CD4 binding to gp120 despite the epitope being distal from the CD4 binding site. Together, these structural, functional and biophysical results suggest that the PGT121 antibodies may interfere with Env receptor engagement by an allosteric mechanism in which key structural elements, such as the V3 base, the N332 oligomannose glycan and surrounding glycans, including a putative V1/V2 complex biantennary glycan, are conformationally constrained.

PubMed: 23658524
DOI: 10.1371/journal.ppat.1003342

実験手法

X-RAY DIFFRACTION (2.8 Å)