PDBsum entry 2git

Immune system

PDB id

2git

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Contents

			Protein chains

					275 a.a. *


					100 a.a. *

			Ligands

					LEU-LEU-PHE-GLY- LYS-PRO-VAL-TYR- VAL ×2


					GOL ×6


					FMT ×9

			Metals

					_NA

			Waters ×788

* Residue conservation analysis

PDB id:

2git

Links

Name:

Immune system

Title:

Human class i mhc hla-a2 in complex with the modified htlv-1 tax (y5k- 4-[3-indolyl]-butyric acid) peptide

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a, d. Fragment: human class i major histocompatibility complex heavy chain. Synonym: mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b, e. Fragment: beta-2-microglobulin. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a, hlaa. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: b2m. Synthetic: yes. Other_details: commercial synthesis for the peptide

Biol. unit:

Trimer (from PQS)

Resolution:

1.70Å

R-factor:

0.182

R-free:

0.219

Authors:

O.Y.Borbulevych,B.M.Baker

Key ref:

S.J.Gagnon et al. (2006). T cell receptor recognition via cooperative conformational plasticity. J Mol Biol, 363, 228-243. PubMed id: 16962135 DOI: 10.1016/j.jmb.2006.08.045

Date:

29-Mar-06

Release date:

03-Oct-06

PROCHECK

	Headers

	References

Protein chains

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

Seq: Struc:					365 a.a. 275 a.a.*

Protein chains

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

Seq: Struc:					119 a.a. 100 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 20 residue positions (black crosses)

DOI no: 10.1016/j.jmb.2006.08.045	J Mol Biol 363:228-243 (2006)
PubMed id: 16962135

T cell receptor recognition via cooperative conformational plasticity.
S.J.Gagnon, O.Y.Borbulevych, R.L.Davis-Harrison, R.V.Turner, M.Damirjian, A.Wojnarowicz, W.E.Biddison, B.M.Baker.

ABSTRACT

Although T cell receptor cross-reactivity is a fundamental property of the immune system and is implicated in numerous autoimmune pathologies, the molecular mechanisms by which T cell receptors can recognize and respond to diverse ligands are incompletely understood. In the current study we examined the response of the human T cell lymphotropic virus-1 (HTLV-1) Tax-specific T cell receptor (TCR) A6 to a panel of structurally distinct haptens coupled to the Tax 11-19 peptide with a lysine substitution at position 5 (Tax5K, LLFG[K-hapten]PVYV). The A6 TCR could cross-reactively recognize one of these haptenated peptides, Tax-5K-4-(3-Indolyl)-butyric acid (IBA), presented by HLA-A*0201. The crystal structures of Tax5K-IBA/HLA-A2 free and in complex with A6 reveal that binding is mediated by a mechanism of cooperative conformational plasticity involving conformational changes on both sides of the protein-protein interface, including the TCR complementarity determining region (CDR) loops, Valpha/Vbeta domain orientation, and the hapten-modified peptide. Our findings illustrate the complex role that protein dynamics can play in TCR cross-reactivity and highlight that T cell receptor recognition of ligand can be achieved through diverse and complex molecular mechanisms that can occur simultaneously in the interface, not limited to molecular mimicry and CDR loop shifts.

Selected figure(s)



	Figure 1. Figure 1. The native Tax peptide (top) and the Tax-5K-IBA peptide (bottom), illustrating the chemical and structural differences between the two position 5 side-chains.		Figure 5. Figure 5. Stereo views of accommodation of the P5 side-chains by the A6 TCR. (a) In the ternary complex, the Lys-IBA side-chain bends around towards the HLA-A2 α2 helix and fits between the A6 CDR3α and CDR3β loops. The peptide is shown in magenta along with 2F[o]–F[c] electron density contoured at 1σ. CDR3β of A6 is in yellow, CDR3α is green; other TCR components are not shown. Three hydrogen bonds are formed between the Lys-IBA side-chain and Arg95 and Gly101 of CDR3β (indicated as hb1, hb2, and hb3). A fourth hydrogen bond (hb4) is formed between the IBA moiety and Gln155 of HLA-A2 (orange). (b) In the structure with the native Tax peptide, the Tyr at P5 fits into a pocket generated by the juxtaposition of CDR3β (blue) and CDR3α (yellow). (c) In the structure with the Tax-5K-IBA peptide, changes in the CDR3 loops and the shift in Vα/Vβ orientation greatly expand the central pocket in order to accommodate the larger side-chain.

Figures were selected by the author.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21173256

H.N.Eisen, and A.K.Chakraborty (2010).
Evolving concepts of specificity in immune reactions.

Proc Natl Acad Sci U S A, 107, 22373-22380.

20927455

M.Tarbe, I.Azcune, E.Balentová, J.J.Miles, E.E.Edwards, K.M.Miles, P.Do, B.M.Baker, A.K.Sewell, J.M.Aizpurua, C.Douat-Casassus, and S.Quideau (2010).
Design, synthesis and evaluation of β-lactam antigenic peptide hybrids; unusual opening of the β-lactam ring in acidic media.

Org Biomol Chem, 8, 5345-5353.

19698083

K.H.Piepenbrink, O.Y.Borbulevych, R.F.Sommese, J.Clemens, K.M.Armstrong, C.Desmond, P.Do, and B.M.Baker (2009).
Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner.

Biochem J, 423, 353-361.

PDB codes:

3d39 3d3v

20064447

O.Y.Borbulevych, K.H.Piepenbrink, B.E.Gloor, D.R.Scott, R.F.Sommese, D.K.Cole, A.K.Sewell, and B.M.Baker (2009).
T cell receptor cross-reactivity directed by antigen-dependent tuning of peptide-MHC molecular flexibility.

Immunity, 31, 885-896.

PDB codes:

3h7b 3h9h 3h9s 3ixa

18726714

E.J.Collins, and D.S.Riddle (2008).
TCR-MHC docking orientation: natural selection, or thymic selection?

Immunol Res, 41, 267-294.

18675271

J.J.Melenhorst, P.Scheinberg, P.K.Chattopadhyay, A.Lissina, E.Gostick, D.K.Cole, L.Wooldridge, H.A.van den Berg, E.Bornstein, N.F.Hensel, D.C.Douek, M.Roederer, A.K.Sewell, A.J.Barrett, and D.A.Price (2008).
Detection of low avidity CD8(+) T cell populations with coreceptor-enhanced peptide-major histocompatibility complex class I tetramers.

J Immunol Methods, 338, 31-39.

18800968

K.M.Armstrong, K.H.Piepenbrink, and B.M.Baker (2008).
Conformational changes and flexibility in T-cell receptor recognition of peptide-MHC complexes.

Biochem J, 415, 183-196.

18094522

H.Tsurui, and T.Takahashi (2007).
Prediction of T-cell epitope.

J Pharmacol Sci, 105, 299-316.

17449678

K.M.Armstrong, and B.M.Baker (2007).
A comprehensive calorimetric investigation of an entropically driven T cell receptor-peptide/major histocompatibility complex interaction.

Biophys J, 93, 597-609.

17719062

O.Y.Borbulevych, F.K.Insaidoo, T.K.Baxter, D.J.Powell, L.A.Johnson, N.P.Restifo, and B.M.Baker (2007).
Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition.

J Mol Biol, 372, 1123-1136.

PDB codes:

2gt9 2gtw 2gtz 2guo

18074396

R.L.Rich, and D.G.Myszka (2007).
Survey of the year 2006 commercial optical biosensor literature.

J Mol Recognit, 20, 300-366.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.