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==Crystal structure of bicyclic peptide UK729 bound as an acyl-enzyme intermediate to urokinase-type plasminogen activator (uPA)== | ==Crystal structure of bicyclic peptide UK729 bound as an acyl-enzyme intermediate to urokinase-type plasminogen activator (uPA)== | ||
<StructureSection load='4mnv' size='340' side='right' caption='[[4mnv]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='4mnv' size='340' side='right'caption='[[4mnv]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4mnv]] is a 3 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4mnv]] 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=4MNV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MNV FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZBR:1,3,5-TRIS(BROMOMETHYL)BENZENE'>ZBR</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZBR:1,3,5-TRIS(BROMOMETHYL)BENZENE'>ZBR</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=4mnv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mnv OCA], [https://pdbe.org/4mnv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mnv RCSB], [https://www.ebi.ac.uk/pdbsum/4mnv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mnv ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN] Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:[https://omim.org/entry/601709 601709]. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.<ref>PMID:20007542</ref> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 24: | Line 20: | ||
</div> | </div> | ||
<div class="pdbe-citations 4mnv" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4mnv" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Plasminogen activator|Plasminogen activator]] | |||
*[[Urokinase 3D Structures|Urokinase 3D Structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Chen | [[Category: Chen S]] | ||
[[Category: Heinis | [[Category: Heinis C]] | ||
[[Category: Pojer | [[Category: Pojer F]] | ||
Revision as of 12:54, 28 December 2022
Crystal structure of bicyclic peptide UK729 bound as an acyl-enzyme intermediate to urokinase-type plasminogen activator (uPA)Crystal structure of bicyclic peptide UK729 bound as an acyl-enzyme intermediate to urokinase-type plasminogen activator (uPA)
Structural highlights
DiseaseUROK_HUMAN Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:601709. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.[1] FunctionUROK_HUMAN Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Publication Abstract from PubMedBicyclic peptides generated through directed evolution by using phage display offer an attractive ligand format for the development of therapeutics. Being nearly 100-fold smaller than antibodies, they promise advantages such as access to chemical synthesis, efficient diffusion into tissues, and needle-free application. However, unlike antibodies, they do not have a folded structure in solution and thus bind less well. We developed bicyclic peptides with hydrophilic chemical structures at their center to promote noncovalent intramolecular interactions, thereby stabilizing the peptide conformation. The sequences of the peptides isolated by phage display from large combinatorial libraries were strongly influenced by the type of small molecule used in the screen, thus suggesting that the peptides fold around the small molecules. X-ray structure analysis revealed that the small molecules indeed formed hydrogen bonds with the peptides. These noncovalent interactions stabilize the peptide-protein complexes and contribute to the high binding affinity. Peptide ligands stabilized by small molecules.,Chen S, Bertoldo D, Angelini A, Pojer F, Heinis C Angew Chem Int Ed Engl. 2014 Feb 3;53(6):1602-6. doi: 10.1002/anie.201309459., Epub 2014 Jan 22. PMID:24453110[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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