1pyw: Difference between revisions

Revision as of 15:34, 21 February 2008

Human class II MHC protein HLA-DR1 bound to a designed peptide related to influenza virus hemagglutinin, FVKQNA(MAA)AL, in complex with staphylococcal enterotoxin C3 variant 3B2 (SEC3-3B2)

OverviewOverview

Crystal structures of the class II major histocompatibilty complex (MHC) protein, HLA-DR1, generally show a tight fit between MHC and bound peptide except in the P6/P7 region of the peptide-binding site. In this region, there is a shallow water-filled pocket underneath the peptide and between the pockets that accommodate the P6 and P7 side chains. We investigated the properties of this pocket with the idea of engineering substitutions into the corresponding region of peptide antigens to increase their binding affinity for HLA-DR1. We investigated d-amino acids and N-alkyl modifications at both the P6 and P7 positions of the peptide and found that binding of peptides to HLA-DR1 could be increased by incorporating an N-methyl substitution at position 7 of the peptide. The crystal structure of HLA-DR1 bound to a peptide containing a P7 N-methyl alanine was determined. The N-methyl group orients in the P6/P7 pocket, displacing one of the waters usually bound in this pocket. The structure shows that the substitution does not alter the conformation of the bound peptide, which adopts the usual polyproline type II helix. An antigenic peptide carrying the N-methyl modification is taken up by antigen-presenting cells and loaded onto endogenous class II MHC molecules for presentation, and the resultant MHC-peptide complexes activate antigen-specific T-cells. These results suggest a possible strategy for increasing the affinity of weakly immunogenic peptides that might be applicable to the development of vaccines and diagnostic reagents.

About this StructureAbout this Structure

1PYW is a Protein complex structure of sequences from Homo sapiens and Staphylococcus aureus with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

Exploration of the P6/P7 region of the peptide-binding site of the human class II major histocompatability complex protein HLA-DR1., Zavala-Ruiz Z, Sundberg EJ, Stone JD, DeOliveira DB, Chan IC, Svendsen J, Mariuzza RA, Stern LJ, J Biol Chem. 2003 Nov 7;278(45):44904-12. Epub 2003 Sep 1. PMID:12952957

Page seeded by OCA on Thu Feb 21 14:34:03 2008

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OCA

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-[[Image:1pyw.gif|left|200px]]<br />
+[[Image:1pyw.gif|left|200px]]<br /><applet load="1pyw" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1pyw" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1pyw, resolution 2.1&Aring;" />
 '''Human class II MHC protein HLA-DR1 bound to a designed peptide related to influenza virus hemagglutinin, FVKQNA(MAA)AL, in complex with staphylococcal enterotoxin C3 variant 3B2 (SEC3-3B2)'''<br />
 ==Overview==
-Crystal structures of the class II major histocompatibilty complex (MHC), protein, HLA-DR1, generally show a tight fit between MHC and bound peptide, except in the P6/P7 region of the peptide-binding site. In this region, there is a shallow water-filled pocket underneath the peptide and between, the pockets that accommodate the P6 and P7 side chains. We investigated, the properties of this pocket with the idea of engineering substitutions, into the corresponding region of peptide antigens to increase their, binding affinity for HLA-DR1. We investigated d-amino acids and N-alkyl, modifications at both the P6 and P7 positions of the peptide and found, that binding of peptides to HLA-DR1 could be increased by incorporating an, N-methyl substitution at position 7 of the peptide. The crystal structure, of HLA-DR1 bound to a peptide containing a P7 N-methyl alanine was, determined. The N-methyl group orients in the P6/P7 pocket, displacing one, of the waters usually bound in this pocket. The structure shows that the, substitution does not alter the conformation of the bound peptide, which, adopts the usual polyproline type II helix. An antigenic peptide carrying, the N-methyl modification is taken up by antigen-presenting cells and, loaded onto endogenous class II MHC molecules for presentation, and the, resultant MHC-peptide complexes activate antigen-specific T-cells. These, results suggest a possible strategy for increasing the affinity of weakly, immunogenic peptides that might be applicable to the development of, vaccines and diagnostic reagents.
+Crystal structures of the class II major histocompatibilty complex (MHC) protein, HLA-DR1, generally show a tight fit between MHC and bound peptide except in the P6/P7 region of the peptide-binding site. In this region, there is a shallow water-filled pocket underneath the peptide and between the pockets that accommodate the P6 and P7 side chains. We investigated the properties of this pocket with the idea of engineering substitutions into the corresponding region of peptide antigens to increase their binding affinity for HLA-DR1. We investigated d-amino acids and N-alkyl modifications at both the P6 and P7 positions of the peptide and found that binding of peptides to HLA-DR1 could be increased by incorporating an N-methyl substitution at position 7 of the peptide. The crystal structure of HLA-DR1 bound to a peptide containing a P7 N-methyl alanine was determined. The N-methyl group orients in the P6/P7 pocket, displacing one of the waters usually bound in this pocket. The structure shows that the substitution does not alter the conformation of the bound peptide, which adopts the usual polyproline type II helix. An antigenic peptide carrying the N-methyl modification is taken up by antigen-presenting cells and loaded onto endogenous class II MHC molecules for presentation, and the resultant MHC-peptide complexes activate antigen-specific T-cells. These results suggest a possible strategy for increasing the affinity of weakly immunogenic peptides that might be applicable to the development of vaccines and diagnostic reagents.
 ==About this Structure==
-PYW is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] with ACE as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1PYW OCA].
+PYW is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] with <scene name='pdbligand=ACE:'>ACE</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PYW OCA].
 ==Reference==
@@ Line 15: / Line 14: @@
 [[Category: Protein complex]]
 [[Category: Staphylococcus aureus]]
-[[Category: Chan, I.C.]]
+[[Category: Chan, I C.]]
-[[Category: DeOliveira, D.B.]]
+[[Category: DeOliveira, D B.]]
-[[Category: Mariuzza, R.A.]]
+[[Category: Mariuzza, R A.]]
-[[Category: Stern, L.J.]]
+[[Category: Stern, L J.]]
-[[Category: Stone, J.D.]]
+[[Category: Stone, J D.]]
-[[Category: Sundberg, E.J.]]
+[[Category: Sundberg, E J.]]
 [[Category: Svendsen, J.]]
 [[Category: Zavala-Ruiz, Z.]]
@@ Line 33: / Line 32: @@
 [[Category: superantigen]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:48:48 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:34:03 2008''