View source for 6rn7


==DPP1 in complex with inhibitor==
<StructureSection load='6rn7' size='340' side='right'caption='[[6rn7]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6rn7]] is a 3 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=6RN7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RN7 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.66&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K9W:(2~{S})-~{N}-[(2~{S})-1-azanyl-3-[4-(4-cyanophenyl)phenyl]propan-2-yl]pyrrolidine-2-carboxamide'>K9W</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=6rn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rn7 OCA], [https://pdbe.org/6rn7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rn7 RCSB], [https://www.ebi.ac.uk/pdbsum/6rn7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rn7 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CATC_HUMAN CATC_HUMAN] Defects in CTSC are a cause of Papillon-Lefevre syndrome (PLS) [MIM:[https://omim.org/entry/245000 245000]; also known as keratosis palmoplantaris with periodontopathia. PLS is an autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees.<ref>PMID:11180601</ref> <ref>PMID:12809647</ref> <ref>PMID:10581027</ref> <ref>PMID:10662808</ref> <ref>PMID:11106356</ref> <ref>PMID:11180012</ref> <ref>PMID:11886537</ref> <ref>PMID:11158173</ref> <ref>PMID:12112662</ref> <ref>PMID:14974080</ref> <ref>PMID:15108292</ref> <ref>PMID:15991336</ref>   Defects in CTSC are a cause of Haim-Munk syndrome (HMS) [MIM:[https://omim.org/entry/245010 245010]; also known as keratosis palmoplantaris with periodontopathia and onychogryposis or Cochin Jewish disorder. HMS is an autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis.<ref>PMID:10662807</ref>   Defects in CTSC are a cause of aggressive periodontititis type 1 (AP1) [MIM:[https://omim.org/entry/170650 170650]; also known as juvenile periodontitis (JPD) and prepubertal periodontitis (PPP). AP1 is characterized by severe and protracted gingival infections, leading to tooth loss. AP1 inheritance is autosomal dominant.<ref>PMID:10662808</ref> <ref>PMID:14974080</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CATC_HUMAN CATC_HUMAN] Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII.<ref>PMID:1586157</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of pyrrolidine amino nitrile DPP1 inhibitors have been developed and characterized. The S2 pocket structure-activity relationship for these compounds shows significant gains in potency for DPP1 from interacting further with target residues and a network of water molecules in the binding pocket. Herein we describe the X-ray crystal structures of several of these compounds alongside an analysis of factors influencing the inhibitory potency toward DPP1 of which stabilization of the water network, demonstrated using Grand Canonical Monte Carlo simulations and free energy calculations, is attributed as a main factor.

DPP1 Inhibitors: Exploring the Role of Water in the S2 Pocket of DPP1 with Substituted Pyrrolidines.,Kack H, Doyle K, Hughes SJ, Bodnarchuk MS, Lonn H, Van De Poel A, Palmer N ACS Med Chem Lett. 2019 Jul 15;10(8):1222-1227. doi:, 10.1021/acsmedchemlett.9b00261. eCollection 2019 Aug 8. PMID:31413809<ref>PMID:31413809</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6rn7" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kack H]]