PDBsum entry 2p5e

Immune system

PDB id

2p5e

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Contents

			Protein chains

					276 a.a. *


					100 a.a. *


					194 a.a. *


					241 a.a. *

			Ligands

					SER-LEU-LEU-MET- TRP-ILE-THR-GLN- CYS


					GOL ×8


					SO4 ×5


					IPA


					EPE

			Metals

					_MG

			Waters ×739

* Residue conservation analysis

PDB id:

2p5e

Links

Name:

Immune system

Title:

Crystal structures of high affinity human t-cell receptors bound to pmhc reveal native diagonal binding geometry

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a. Fragment: extracellular domains alpha 1, alpha2 and alpha3, residues 25-299. Synonym: mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b. Fragment: beta-2 microglobulin, residues 21-119.

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: this sequence occurs naturally in homo sapiens

Resolution:

1.89Å

R-factor:

0.181

R-free:

0.236

Authors:

M.Sami,P.J.Rizkallah,S.Dunn,Y.Li,R.Moysey,A.Vuidepot,E.Baston, P.Todorov,P.Molloy,F.Gao,J.M.Boulter,B.K.Jakobsen

Key ref:

M.Sami et al. (2007). Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry. Protein Eng Des Sel, 20, 397-403. PubMed id: 17644531

Date:

15-Mar-07

Release date:

25-Sep-07

PROCHECK

	Headers

	References

Protein chain

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

Seq: Struc:					365 a.a. 276 a.a.*

Protein chain

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

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

Protein chain

P01848 (TCA_HUMAN) - T cell receptor alpha chain constant from Homo sapiens

Seq: Struc:					140 a.a. 194 a.a.*

Protein chain

No UniProt id for this chain

Struc:					241 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 23 residue positions (black crosses)

	Protein Eng Des Sel 20:397-403 (2007)
PubMed id: 17644531

Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry.
M.Sami, P.J.Rizkallah, S.Dunn, P.Molloy, R.Moysey, A.Vuidepot, E.Baston, P.Todorov, Y.Li, F.Gao, J.M.Boulter, B.K.Jakobsen.

ABSTRACT

Naturally selected T-cell receptors (TCRs) are characterised by low binding affinities, typically in the range 1-100 microM. Crystal structures of syngeneic TCRs bound to peptide major histocompatibility complex (pMHC) antigens exhibit a conserved mode of binding characterised by a distinct diagonal binding geometry, with poor shape complementarity (SC) between receptor and ligand. Here, we report the structures of three in vitro affinity enhanced TCRs that recognise the pMHC tumour epitope NY-ESO(157-165) (SLLMWITQC). These crystal structures reveal that the docking mode for the high affinity TCRs is identical to that reported for the parental wild-type TCR, with only subtle changes in the mutated complementarity determining regions (CDRs) that form contacts with pMHC; both CDR2 and CDR3 mutations act synergistically to improve the overall affinity. Comparison of free and bound TCR structures for both wild-type and a CDR3 mutant reveal an induced fit mechanism arising from restructuring of CDR3 loops which allows better peptide binding. Overall, an increased interface area, improved SC and additional H-bonding interactions are observed, accounting for the increase in affinity. Most notably, there is a marked increase in the SC for the central methionine and tryptophan peptide motif over the native TCR.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21159619

D.H.Aggen, A.S.Chervin, F.K.Insaidoo, K.H.Piepenbrink, B.M.Baker, and D.M.Kranz (2011).
Identification and engineering of human variable regions that allow expression of stable single-chain T cell receptors.

Protein Eng Des Sel, 24, 361-372.

18767161

J.N.Haidar, B.Pierce, Y.Yu, W.Tong, M.Li, and Z.Weng (2009).
Structure-based design of a T-cell receptor leads to nearly 100-fold improvement in binding affinity for pepMHC.

Proteins, 74, 948-960.

19148199

K.C.Garcia, J.J.Adams, D.Feng, and L.K.Ely (2009).
The molecular basis of TCR germline bias for MHC is surprisingly simple.

Nat Immunol, 10, 143-147.

18726714

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

Immunol Res, 41, 267-294.

18809922

L.Derré, M.Bruyninx, P.Baumgaertner, M.Ferber, D.Schmid, A.Leimgruber, V.Zoete, P.Romero, O.Michielin, D.E.Speiser, and N.Rufer (2008).
Distinct sets of alphabeta TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues.

Proc Natl Acad Sci U S A, 105, 15010-15015.

18424733

P.F.Robbins, Y.F.Li, M.El-Gamil, Y.Zhao, J.A.Wargo, Z.Zheng, H.Xu, R.A.Morgan, S.A.Feldman, L.A.Johnson, A.D.Bennett, S.M.Dunn, T.M.Mahon, B.K.Jakobsen, and S.A.Rosenberg (2008).
Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions.

J Immunol, 180, 6116-6131.

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.