PDBsum entry 4hv8

Immune system

PDB id: 4hv8

Contents

Protein chains

276 a.a.

100 a.a.

Ligands

ALA-SER-ASN-GLU-ASN-ILE-GLU-THR-MET ×2

SO4 ×6

Waters ×830

PDB id:

4hv8

Name:

Immune system

Title:

Crystal structure of h2db-h155a-npm6i

Structure:

H-2 class i histocompatibility antigen, d-b alpha chain. Chain: a, c. Synonym: h-2d(b). Engineered: yes. Mutation: yes. Beta-2-microglobulin. Chain: b, d. Engineered: yes. Npm6i variant peptide.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: h2-d1. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: b2m. Synthetic: yes

Resolution:

2.00Å R-factor: 0.184 R-free: 0.236

Authors:

S.Gras,K.A.Twist,J.Rossjohn

Key ref:

S.A.Valkenburg et al. (2013). Preemptive priming readily overcomes structure-based mechanisms of virus escape. Proc Natl Acad Sci U S A, 110, 5570-5575. PubMed id: 23493558 DOI: 10.1073/pnas.1302935110

Date:

05-Nov-12 Release date: 27-Feb-13

Protein chains

P01899  (HA11_MOUSE) -  H-2 class I histocompatibility antigen, D-B alpha chain from Mus musculus

Seq: 362 a.a.

Struc: 276 a.a.*

Protein chains

P01887  (B2MG_MOUSE) -  Beta-2-microglobulin from Mus musculus

Seq: 119 a.a.

Struc: 100 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1073/pnas.1302935110

Proc Natl Acad Sci U S A 110:5570-5575 (2013)

PubMed id: 23493558

Preemptive priming readily overcomes structure-based mechanisms of virus escape.

S.A.Valkenburg, S.Gras, C.Guillonneau, L.A.Hatton, N.A.Bird, K.A.Twist, H.Halim, D.C.Jackson, A.W.Purcell, S.J.Turner, P.C.Doherty, J.Rossjohn, K.Kedzierska.

ABSTRACT

A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial "hole" in the naïve T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.