PDBsum entry 1s9x

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Immune system PDB id
Protein chains
274 a.a. *
100 a.a. *
Waters ×168
* Residue conservation analysis
PDB id:
Name: Immune system
Title: Crystal structure analysis of ny-eso-1 epitope analogue, sllmwitqa, in complex with hla-a2
Structure: Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a. Fragment: extracellular domains alpha1, alpha2, alpha3. Synonym: hla-a2, mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b. Synonym: beta2 microglobulin, hdcma22p.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic peptide
Biol. unit: Trimer (from PQS)
2.50Å     R-factor:   0.230     R-free:   0.279
Authors: A.I.Webb,M.A.Dunstone,W.Chen,M.I.Aguilar,Q.Chen,L.Chang, L.Kjer-Nielsen,T.Beddoe,J.Mccluskey,J.Rossjohn,A.W.Purcell
Key ref:
A.I.Webb et al. (2004). Functional and structural characteristics of NY-ESO-1-related HLA A2-restricted epitopes and the design of a novel immunogenic analogue. J Biol Chem, 279, 23438-23446. PubMed id: 15004033 DOI: 10.1074/jbc.M314066200
05-Feb-04     Release date:   28-Sep-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P01892  (1A02_HUMAN) -  HLA class I histocompatibility antigen, A-2 alpha chain
365 a.a.
274 a.a.
Protein chain
Pfam   ArchSchema ?
P61769  (B2MG_HUMAN) -  Beta-2-microglobulin
119 a.a.
100 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   16 terms 
  Biological process     immune system process   22 terms 
  Biochemical function     protein binding     3 terms  


DOI no: 10.1074/jbc.M314066200 J Biol Chem 279:23438-23446 (2004)
PubMed id: 15004033  
Functional and structural characteristics of NY-ESO-1-related HLA A2-restricted epitopes and the design of a novel immunogenic analogue.
A.I.Webb, M.A.Dunstone, W.Chen, M.I.Aguilar, Q.Chen, H.Jackson, L.Chang, L.Kjer-Nielsen, T.Beddoe, J.McCluskey, J.Rossjohn, A.W.Purcell.
NY-ESO-1, a commonly expressed tumor antigen of the cancer-testis family, is expressed by a wide range of tumors but not found in normal adult somatic tissue, making it an ideal cancer vaccine candidate. Peptides derived from NY-ESO-1 have shown preclinical and clinical trial promise; however, biochemical features of these peptides have complicated their formulation and led to heterogeneous immune responses. We have taken a rational approach to engineer an HLA A2-restricted NY-ESO-1-derived T cell epitope with improved formulation and immunogenicity to the wild type peptide. To accomplish this, we have solved the x-ray crystallographic structures of HLA A2 complexed to NY-ESO (157-165) and two analogues of this peptide in which the C-terminal cysteine residue has been substituted to alanine or serine. Substitution of cysteine by serine maintained peptide conformation yet reduced complex stability, resulting in poor cytotoxic T lymphocyte recognition. Conversely, substitution with alanine maintained complex stability and cytotoxic T lymphocyte recognition. Based on the structures of the three HLA A2 complexes, we incorporated 2-aminoisobutyric acid, an isostereomer of cysteine, into the epitope. This analogue is impervious to oxidative damage, cysteinylation, and dimerization of the peptide epitope upon formulation that is characteristic of the wild type peptide. Therefore, this approach has yielded a potential therapeutic molecule that satiates the hydrophobic F pocket of HLA A2 and exhibited superior immunogenicity relative to the wild type peptide.
  Selected figure(s)  
Figure 2.
FIG. 2. Image of the cleft contacts made between the HLA A2 heavy chain and the NY-ESO (157-165) peptide with hydrogen bond contacts only shown. Numerous hydrogen bond and van der Waals contacts exist between the peptide and the HLA A2 cleft residues, including anchoring interactions between P2-Leu and B pocket residues and P9-Cys and F pocket residues. These interactions are summarized in Table III. A large number of peptide-main chain hydrogen bond interactions were observed for this complex relative to other HLA A2 complexes (45, 46), which tend to have more water-mediated hydrogen bonding networks.
Figure 3.
FIG. 3. Differences in peptide conformation are mainly restricted to the terminal functional groups of the P9 amino acid. Detailed view of the F-pocket interactions between the C-terminal cysteine 9, serine 9, and alanine 9 of the wild type, C9S, and C9A analogues of the NY-ESO (157-165) peptide.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 23438-23446) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21332270 N.P.Croft, and A.W.Purcell (2011).
Peptidomimetics: modifying peptides in the pursuit of better vaccines.
  Expert Rev Vaccines, 10, 211-226.  
20137987 M.Aleksic, O.Dushek, H.Zhang, E.Shenderov, J.L.Chen, V.Cerundolo, D.Coombs, and P.A.van der Merwe (2010).
Dependence of T cell antigen recognition on T cell receptor-peptide MHC confinement time.
  Immunity, 32, 163-174.  
19394336 A.J.Gehring, Z.Z.Ho, A.T.Tan, M.O.Aung, K.H.Lee, K.C.Tan, S.G.Lim, and A.Bertoletti (2009).
Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma.
  Gastroenterology, 137, 682-690.  
19196958 J.Petersen, S.J.Wurzbacher, N.A.Williamson, S.H.Ramarathinam, H.H.Reid, A.K.Nair, A.Y.Zhao, R.Nastovska, G.Rudge, J.Rossjohn, and A.W.Purcell (2009).
Phosphorylated self-peptides alter human leukocyte antigen class I-restricted antigen presentation and generate tumor-specific epitopes.
  Proc Natl Acad Sci U S A, 106, 2776-2781.
PDB codes: 3fqn 3fqr 3fqt 3fqu 3fqw 3fqx
19593772 X.Shang, L.Wang, W.Niu, G.Meng, X.Fu, B.Ni, Z.Lin, Z.Yang, X.Chen, and Y.Wu (2009).
Rational optimization of tumor epitopes using in silico analysis-assisted substitution of TCR contact residues.
  Eur J Immunol, 39, 2248-2258.  
18546142 J.Garcia Casado, J.Janda, J.Wei, L.Chapatte, S.Colombetti, P.Alves, G.Ritter, M.Ayyoub, D.Valmori, W.Chen, and F.Lévy (2008).
Lentivector immunization induces tumor antigen-specific B and T cell responses in vivo.
  Eur J Immunol, 38, 1867-1876.  
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.  
19079589 M.Gómez-Nuñez, K.J.Haro, T.Dao, D.Chau, A.Won, S.Escobar-Alvarez, V.Zakhaleva, T.Korontsvit, D.Y.Gin, and D.A.Scheinberg (2008).
Non-natural and photo-reactive amino acids as biochemical probes of immune function.
  PLoS ONE, 3, e3938.  
18949029 N.S.Butler, A.Theodossis, A.I.Webb, R.Nastovska, S.H.Ramarathinam, M.A.Dunstone, J.Rossjohn, A.W.Purcell, and S.Perlman (2008).
Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant.
  PLoS Pathog, 4, e1000186.
PDB codes: 2zsv 2zsw
17011774 C.S.Clements, M.A.Dunstone, W.A.Macdonald, J.McCluskey, and J.Rossjohn (2006).
Specificity on a knife-edge: the alphabeta T cell receptor.
  Curr Opin Struct Biol, 16, 787-795.  
16646078 L.J.Smyth, E.Elkord, T.E.Taher, H.R.Jiang, D.J.Burt, A.Clayton, P.A.van Veelen, Ru, F.Ossendorp, C.J.Melief, J.W.Drijfhout, S.Dermime, R.E.Hawkins, and P.L.Stern (2006).
CD8 T-cell recognition of human 5T4 oncofetal antigen.
  Int J Cancer, 119, 1638-1647.  
17005729 N.A.Williamson, J.Rossjohn, and A.W.Purcell (2006).
Tumors reveal their secrets to cytotoxic T cells.
  Proc Natl Acad Sci U S A, 103, 14649-14650.  
15837811 J.L.Chen, G.Stewart-Jones, G.Bossi, N.M.Lissin, L.Wooldridge, E.M.Choi, G.Held, P.R.Dunbar, R.M.Esnouf, M.Sami, J.M.Boulter, P.Rizkallah, C.Renner, A.Sewell, P.A.van der Merwe, B.K.Jakobsen, G.Griffiths, E.Y.Jones, and V.Cerundolo (2005).
Structural and kinetic basis for heightened immunogenicity of T cell vaccines.
  J Exp Med, 201, 1243-1255.
PDB codes: 2bnq 2bnr 2bnu
  15814707 O.Y.Borbulevych, T.K.Baxter, Z.Yu, N.P.Restifo, and B.M.Baker (2005).
Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design.
  J Immunol, 174, 4812-4820.
PDB codes: 1tvb 1tvh
15469407 S.H.Shoshan, and A.Admon (2004).
MHC-bound antigens and proteomics for novel target discovery.
  Pharmacogenomics, 5, 845-859.  
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.