6eop: Difference between revisions
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==DPP8 - SLRFLYEG, space group 20== | ==DPP8 - SLRFLYEG, space group 20== | ||
<StructureSection load='6eop' size='340' side='right' caption='[[6eop]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='6eop' size='340' side='right'caption='[[6eop]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6eop]] is a 6 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6eop]] is a 6 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=6EOP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EOP FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=F15:PENTADECANOIC+ACID'>F15</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</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=6eop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eop OCA], [https://pdbe.org/6eop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eop RCSB], [https://www.ebi.ac.uk/pdbsum/6eop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eop ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6eop" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6eop" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Dipeptidyl peptidase 3D structures|Dipeptidyl peptidase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Huber | [[Category: Huber R]] | ||
[[Category: Ross | [[Category: Ross BR]] | ||
Latest revision as of 10:55, 17 October 2024
DPP8 - SLRFLYEG, space group 20DPP8 - SLRFLYEG, space group 20
Structural highlights
Publication Abstract from PubMedDipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl peptidases (preferentially postproline) associated with pathophysiological roles in immune response and cancer biology. While the DPP family member DPP4 is extensively characterized in molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures and ligand-/substrate-binding modes of DPP8 and DPP9 have not been reported. In this study we describe crystal and molecular structures of human DPP8 (2.5 A) and DPP9 (3.0 A) unliganded and complexed with a noncanonical substrate and a small molecule inhibitor, respectively. Similar to DPP4, DPP8 and DPP9 molecules consist of one beta-propeller and alpha/beta hydrolase domain, forming a functional homodimer. However, they differ extensively in the ligand binding site structure. In intriguing contrast to DPP4, where liganded and unliganded forms are closely similar, ligand binding to DPP8/9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an alpha-helix (R-helix), including R160/133, a key residue for substrate binding. As vestiges of this helix are also seen in one of the copies of the unliganded form, conformational selection may contributes to ligand binding. Molecular dynamics simulations support increased flexibility of the R-helix in the unliganded state. Consistently, enzyme kinetics assays reveal a cooperative allosteric mechanism. DPP8 and DPP9 are closely similar and display few opportunities for targeted ligand design. However, extensive differences from DPP4 provide multiple cues for specific inhibitor design and development of the DPP family members as therapeutic targets or antitargets. Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer.,Ross B, Krapp S, Augustin M, Kierfersauer R, Arciniega M, Geiss-Friedlander R, Huber R Proc Natl Acad Sci U S A. 2018 Jan 30. pii: 1717565115. doi:, 10.1073/pnas.1717565115. PMID:29382749[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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