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2vnt

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Revision as of 21:21, 19 September 2018

UROKINASE-TYPE PLASMINOGEN ACTIVATOR INHIBITOR COMPLEX WITH A 1-(7- SULPHOAMIDOISOQUINOLINYL)GUANIDINE

Structural highlights

2vnt is a 6 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 2jde. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2viv, 1c5x, 1gj9, 2vio, 2vip, 1w0z, 1fv9, 1vja, 1gj8, 1w11, 1sqo, 1gjd, 1w10, 1owk, 1w12, 1gi9, 1o5a, 1c5z, 1owj, 1gi7, 1o5b, 1gjc, 1sc8, 1gja, 1o3p, 1owe, 1sqa, 1gjb, 2viw, 1f92, 1owi, 1kdu, 2vin, 1sqt, 1f5l, 1owd, 1ejn, 2viq, 1lmw, 1u6q, 1gi8, 1c5y, 1w14, 1vj9, 1w13, 1gj7, 1c5w, 1owh, 1o5c
Activity:	U-plasminogen activator, with EC number 3.4.21.73
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

1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.

Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.,Fish PV, Barber CG, Brown DG, Butt R, Collis MG, Dickinson RP, Henry BT, Horne VA, Huggins JP, King E, O'Gara M, McCleverty D, McIntosh F, Phillips C, Webster R J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21. PMID:17447747^[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
↑ Fish PV, Barber CG, Brown DG, Butt R, Collis MG, Dickinson RP, Henry BT, Horne VA, Huggins JP, King E, O'Gara M, McCleverty D, McIntosh F, Phillips C, Webster R. Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21. PMID:17447747 doi:10.1021/jm061066t

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/2vnt"

@@ Line 1: / Line 1: @@
-==UROKINASE-TYPE PLASMINOGEN ACTIVATOR INHIBITOR COMPLEX WITH A 1-(7-SULPHOAMIDOISOQUINOLINYL)GUANIDINE==
+==UROKINASE-TYPE PLASMINOGEN ACTIVATOR INHIBITOR COMPLEX WITH A 1-(7- SULPHOAMIDOISOQUINOLINYL)GUANIDINE==
 <StructureSection load='2vnt' size='340' side='right' caption='[[2vnt]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
@@ Line 17: / Line 17: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vn/2vnt_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vn/2vnt_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>

2vnt

From Proteopedia

Revision as of 21:21, 19 September 2018

UROKINASE-TYPE PLASMINOGEN ACTIVATOR INHIBITOR COMPLEX WITH A 1-(7- SULPHOAMIDOISOQUINOLINYL)GUANIDINE

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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