7oz7: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, L84== | ==Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, L84== | ||
<StructureSection load='7oz7' size='340' side='right'caption='[[7oz7]]' scene=''> | <StructureSection load='7oz7' size='340' side='right'caption='[[7oz7]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OZ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OZ7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7oz7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OZ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OZ7 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7oz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oz7 OCA], [https://pdbe.org/7oz7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oz7 RCSB], [https://www.ebi.ac.uk/pdbsum/7oz7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oz7 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MQ2:~{N}-[3-[[4-[(4-bromophenyl)methyl]piperazin-1-yl]methyl]phenyl]-2-ethyl-2-methanoyl-butanamide'>MQ2</scene>, <scene name='pdbligand=TMO:TRIMETHYLAMINE+OXIDE'>TMO</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7oz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oz7 OCA], [https://pdbe.org/7oz7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oz7 RCSB], [https://www.ebi.ac.uk/pdbsum/7oz7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oz7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/DPP8_HUMAN DPP8_HUMAN]] Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. May play a role in T-cell activation and immune function.<ref>PMID:11012666</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date. | |||
Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.,Carvalho LAR, Ross B, Fehr L, Bolgi O, Wohrle S, Lum KM, Podlesainski D, Vieira AC, Kiefersauer R, Felix R, Rodrigues T, Lucas SD, Gross O, Geiss-Friedlander R, Cravatt BF, Huber R, Kaiser M, Moreira R Angew Chem Int Ed Engl. 2022 Sep 11. doi: 10.1002/anie.202210498. PMID:36089535<ref>PMID:36089535</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7oz7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Huber R]] | [[Category: Huber R]] | ||
[[Category: Ross B]] | [[Category: Ross B]] | ||
Revision as of 09:26, 28 September 2022
Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, L84Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, L84
Structural highlights
Function[DPP8_HUMAN] Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. May play a role in T-cell activation and immune function.[1] Publication Abstract from PubMedDipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date. Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.,Carvalho LAR, Ross B, Fehr L, Bolgi O, Wohrle S, Lum KM, Podlesainski D, Vieira AC, Kiefersauer R, Felix R, Rodrigues T, Lucas SD, Gross O, Geiss-Friedlander R, Cravatt BF, Huber R, Kaiser M, Moreira R Angew Chem Int Ed Engl. 2022 Sep 11. doi: 10.1002/anie.202210498. PMID:36089535[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||