PDBsum entry 2uwe

Immune system

PDB id: 2uwe

Contents

Protein chains

275 a.a. *

100 a.a. *

194 a.a. *

237 a.a. *

Ligands

ALA-LEU-TRP-GLY-PHE-PHE-PRO-VAL-LEU ×2

Waters ×210

* Residue conservation analysis

PDB id:

2uwe

Name:

Immune system

Title:

Large cdr3a loop alteration as a function of mhc mutation

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a, h. Fragment: ecto-domain, residues 25-299. Synonym: hla-a201, mhc class i antigen a 2. Engineered: yes. Mutation: yes. Other_details: mutation of hla-a2.1 at position 163, threonine to alanine. Beta-2-microglobulin.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Variant: t163a. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: ril. Synthetic: yes. Mus musculus.

Resolution:

2.40Å R-factor: 0.243 R-free: 0.290

Authors:

P.J.Miller,Y.Pazy,B.Conti,D.Riddle,W.E.Biddison,E.Appella,E.J.Collins

Key ref:

P.J.Miller et al. (2007). Single MHC mutation eliminates enthalpy associated with T cell receptor binding. J Mol Biol, 373, 315-327. PubMed id: 17825839 DOI: 10.1016/j.jmb.2007.07.028

Date:

20-Mar-07 Release date: 25-Sep-07

Protein chains

P04439  (1A03_HUMAN) -  HLA class I histocompatibility antigen, A alpha chain from Homo sapiens

Seq: 365 a.a.

Struc: 275 a.a.*

Protein chains

P61769  (B2MG_HUMAN) -  Beta-2-microglobulin from Homo sapiens

Seq: 119 a.a.

Struc: 100 a.a.*

Protein chains

No UniProt id for this chain

Struc: 194 a.a.

Protein chains

P04213  (TVB5_MOUSE) -  T-cell receptor beta chain V region C5 (Fragment) from Mus musculus

Seq: 122 a.a.

Struc: 237 a.a.*

* PDB and UniProt seqs differ at 28 residue positions (black crosses)

DOI no: 10.1016/j.jmb.2007.07.028

J Mol Biol 373:315-327 (2007)

PubMed id: 17825839

Single MHC mutation eliminates enthalpy associated with T cell receptor binding.

P.J.Miller, Y.Pazy, B.Conti, D.Riddle, E.Appella, E.J.Collins.

ABSTRACT

The keystone of the adaptive immune response is T cell receptor (TCR) recognition of peptide presented by major histocompatibility complex (pMHC) molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a large interface with an atypical binding orientation. MHC mutations in the interface of the proteins were tested for changes in TCR recognition. From the range of responses observed, three representative HLA-A2 mutants, T163A, W167A, and K66A, were selected for further study. Binding constants and co-crystal structures of the AHIII TCR and the three mutants were determined. K66 in HLA-A2 makes contacts with both peptide and TCR, and has been identified as a critical residue for recognition by numerous TCR. The K66A mutation resulted in the lowest AHIII T cell response and the lowest binding affinity, which suggests that the T cell response may correlate with affinity. Importantly, the K66A mutation does not affect the conformation of the peptide. The change in affinity appears to be due to a loss in hydrogen bonds in the interface as a result of a conformational change in the TCR complementarity-determining region 3 (CDR3) loop. Isothermal titration calorimetry confirmed the loss of hydrogen bonding by a large loss in enthalpy. Our findings are inconsistent with the notion that the CDR1 and CDR2 loops of the TCR are responsible for MHC restriction, while the CDR3 loops interact solely with the peptide. Instead, we present here an MHC mutation that does not change the conformation of the peptide, yet results in an altered conformation of a CDR3.

Selected figure(s)

Figure 1.
Figure 1. CTL killing as a function of mutations in the p1049/A2 Complex. Cytotoxic lysis assays (^51Cr release assays) were performed with AHIII T cells against cells expressing mutant A2. Data were normalized such that lytic activity against native HLA-A2 is 100%.

Figure 3.
Figure 3. Structure of AHIII TCR bound to p1049/A2. The AHIII TCR α (green) and β (blue) chains, interact with the p1049/A2 surface via CDR loops. pMHC, consisting of a heavy chain, A2, (yellow) and β[2]m (magenta), present the peptide, p1049 (red). (Inset) The surface of the p1049/A2 is contacted by the CDR loops of the AHIII TCR. Residues that have been mutated to alanine for structural experiments (T163, W167, K66) are shown. The Figure was generated using PDB coordinates 1LP9 and PyMol [http://pymol.sourceforge.net/].

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2007, 373, 315-327) copyright 2007.

Figures were selected by an automated process.