PDBsum entry 4npy

Immune system

PDB id: 4npy

Contents

Protein chains

212 a.a.

232 a.a.

Ligands

GOL ×3

Waters ×610

PDB id:

4npy

Name:

Immune system

Title:

Crystal structure of germline fab pgt121, a putative precursor of the broadly reactive and potent HIV-1 neutralizing antibody

Structure:

Germline pgt121 light chain. Chain: l, a. Fragment: fab. Engineered: yes. Germline pgt121 heavy chain. Chain: h, b. Fragment: fab. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek. Expression_system_cell_line: hek

Resolution:

1.80Å R-factor: 0.184 R-free: 0.220

Authors:

J.-P.Julien,D.C.Diwanji,I.A.Wilson

Key ref:

D.Sok et al. (2013). The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. Plos Pathog, 9, e1003754. PubMed id: 24278016 DOI: 10.1371/journal.ppat.1003754

Date:

22-Nov-13 Release date: 11-Dec-13

Protein chains

Q6GMX6  (Q6GMX6_HUMAN) -  IGH@ protein from Homo sapiens

Seq: 465 a.a.

Struc: 212 a.a.*

Protein chains

Q6GMX6  (Q6GMX6_HUMAN) -  IGH@ protein from Homo sapiens

Seq: 465 a.a.

Struc: 232 a.a.*

* PDB and UniProt seqs differ at 172 residue positions (black crosses)

DOI no: 10.1371/journal.ppat.1003754

Plos Pathog 9:e1003754 (2013)

PubMed id: 24278016

The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.

D.Sok, U.Laserson, J.Laserson, Y.Liu, F.Vigneault, J.P.Julien, B.Briney, A.Ramos, K.F.Saye, K.Le, A.Mahan, S.Wang, M.Kardar, G.Yaari, L.M.Walker, B.B.Simen, E.P.St John, P.Y.Chan-Hui, K.Swiderek, S.H.Kleinstein, S.H.Kleinstein, G.Alter, M.S.Seaman, A.K.Chakraborty, D.Koller, I.A.Wilson, G.M.Church, D.R.Burton, P.Poignard.

ABSTRACT

Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121-134 but were still capable of neutralizing roughly 40-80% of PGT121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121-134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121-134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.