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4jbs

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Revision as of 17:13, 4 August 2016

Crystal structure of the human Endoplasmic Reticulum Aminopeptidase 2 in complex with PHOSPHINIC PSEUDOTRIPEPTIDE inhibitor.

Structural highlights

4jbs is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	4e36, 3se6
Gene:	ERAP2, LRAP (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ERAP2_HUMAN] Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Preferentially hydrolyzes the basic residues Arg and Lys.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy. In this study we exploited recent structural and biochemical analysis of ERAP1 and ERAP2 to design and develop phosphinic pseudopeptide transition state analogs that can inhibit this family of enzymes with nM affinity. X-ray crystallographic analysis of one such inhibitor in complex with ERAP2 validated our design, revealing a canonical mode of binding in the active site of the enzyme, and highlighted the importance of the S2' pocket for achieving inhibitor potency. Antigen processing and presentation assays in HeLa and murine colon carcinoma (CT26) cells showed that these inhibitors induce increased cell-surface antigen presentation of transfected and endogenous antigens and enhance cytotoxic T-cell responses, indicating that these enzymes primarily destroy epitopes in those systems. This class of inhibitors constitutes a promising tool for controlling the cellular adaptive immune response in humans by modulating the antigen processing and presentation pathway.

Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses.,Zervoudi E, Saridakis E, Birtley JR, Seregin SS, Reeves E, Kokkala P, Aldhamen YA, Amalfitano A, Mavridis IM, James E, Georgiadis D, Stratikos E Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19890-5. doi:, 10.1073/pnas.1309781110. Epub 2013 Nov 18. PMID:24248368^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tanioka T, Hattori A, Masuda S, Nomura Y, Nakayama H, Mizutani S, Tsujimoto M. Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases. J Biol Chem. 2003 Aug 22;278(34):32275-83. Epub 2003 Jun 10. PMID:12799365 doi:http://dx.doi.org/10.1074/jbc.M305076200
↑ Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, Greer F, Schomburg L, Fruci D, Niedermann G, van Endert PM. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005 Jul;6(7):689-97. Epub 2005 May 22. PMID:15908954 doi:http://dx.doi.org/10.1038/ni1208
↑ Chang SC, Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17107-12. Epub 2005 Nov 14. PMID:16286653 doi:http://dx.doi.org/0500721102
↑ Zervoudi E, Saridakis E, Birtley JR, Seregin SS, Reeves E, Kokkala P, Aldhamen YA, Amalfitano A, Mavridis IM, James E, Georgiadis D, Stratikos E. Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses. Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19890-5. doi:, 10.1073/pnas.1309781110. Epub 2013 Nov 18. PMID:24248368 doi:http://dx.doi.org/10.1073/pnas.1309781110

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4jbs"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the human Endoplasmic Reticulum Aminopeptidase 2 in complex with PHOSPHINIC PSEUDOTRIPEPTIDE inhibitor.==
 <StructureSection load='4jbs' size='340' side='right' caption='[[4jbs]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4e36|4e36]], [[3se6|3se6]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ERAP2, LRAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jbs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jbs OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jbs RCSB], [http://www.ebi.ac.uk/pdbsum/4jbs PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jbs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jbs OCA], [http://pdbe.org/4jbs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jbs RCSB], [http://www.ebi.ac.uk/pdbsum/4jbs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jbs ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4jbs" style="background-color:#fffaf0;"></div>
 ==See Also==

4jbs

From Proteopedia

Revision as of 17:13, 4 August 2016

Crystal structure of the human Endoplasmic Reticulum Aminopeptidase 2 in complex with PHOSPHINIC PSEUDOTRIPEPTIDE inhibitor.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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