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2nwn

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Revision as of 06:36, 20 May 2020

New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1

Structural highlights

2nwn 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.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[UROK_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]

Function

[UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Urokinase-type plasminogen activator (uPA) plays a crucial role in the regulation of plasminogen activation, tumor cell adhesion and migration. The inhibition of uPA activity is a promising mechanism for anti-cancer therapy. A cyclic peptidyl inhibitor, upain-1, CSWRGLENHRMC, was identified recently as a competitive and highly specific uPA inhibitor. We determined the crystal structure of uPA in complex with upain-1 at 2.15 A. The structure reveals that the cyclic peptide adopts a rigid conformation stabilized by a disulfide bond (residues 1-12) and three tight beta turns (residues 3-6, 6-9, 9-12). The Glu7 residue of upain-1 forms hydrogen bonds with the main chain nitrogen atoms of residues 4, 5, and 6 of upain-1, and is also critical for maintaining the active conformation of upain-1. The Arg4 of upain-1 is inserted into the uPA's specific S1 pocket. The Ser2 residue of upain-1 locates close to the S1beta pocket of uPA. The Gly5 and Glu7 residues of upain-1 occupy the S2 pocket and the oxyanion hole of uPA, respectively. Furthermore, the Asn8 residue of upain-1 binds to the 37- and 60-loops of uPA and renders the specificity of upain-1 for uPA. Based on this structure, a new pharmacophore for the design of highly specific uPA inhibitors was proposed.

Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1.,Zhao G, Yuan C, Wind T, Huang Z, Andreasen PA, Huang M J Struct Biol. 2007 Oct;160(1):1-10. Epub 2007 Jun 20. PMID:17692534^[2]

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

References

↑ Paterson AD, Rommens JM, Bharaj B, Blavignac J, Wong I, Diamandis M, Waye JS, Rivard GE, Hayward CP. Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene. Blood. 2010 Feb 11;115(6):1264-6. doi: 10.1182/blood-2009-07-233965. Epub 2009, Dec 9. PMID:20007542 doi:10.1182/blood-2009-07-233965
↑ Zhao G, Yuan C, Wind T, Huang Z, Andreasen PA, Huang M. Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1. J Struct Biol. 2007 Oct;160(1):1-10. Epub 2007 Jun 20. PMID:17692534 doi:10.1016/j.jsb.2007.06.003

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2nwn"

@@ Line 1: / Line 1: @@
 ==New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1==
-<StructureSection load='2nwn' size='340' side='right' caption='[[2nwn]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
+<StructureSection load='2nwn' size='340' side='right'caption='[[2nwn]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2nwn]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NWN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2NWN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2nwn]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NWN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2NWN FirstGlance]. <br>
-</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=2nwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nwn OCA], [http://pdbe.org/2nwn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2nwn RCSB], [http://www.ebi.ac.uk/pdbsum/2nwn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2nwn ProSAT]</span></td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2nwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nwn OCA], [http://pdbe.org/2nwn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2nwn RCSB], [http://www.ebi.ac.uk/pdbsum/2nwn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2nwn ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 31: / Line 31: @@
 ==See Also==
-*[[Urokinase|Urokinase]]
+*[[Urokinase 3D Structures|Urokinase 3D Structures]]
 == References ==
 <references/>
@@ Line 37: / Line 37: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Andreasen, P A]]
 [[Category: Huang, M]]

2nwn

From Proteopedia

Revision as of 06:36, 20 May 2020

New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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