1fv9: Difference between revisions

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New page: left|200px<br /> <applet load="1fv9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fv9, resolution 3.00Å" /> '''Crystal structure o...
 
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[[Image:1fv9.gif|left|200px]]<br />
<applet load="1fv9" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1fv9, resolution 3.00&Aring;" />
'''Crystal structure of human microurokinase in complex with 2-amino-5-hydroxy-benzimidazole'''<br />


==Overview==
==Crystal structure of human microurokinase in complex with 2-amino-5-hydroxy-benzimidazole==
Using an NMR-based screen, a novel class of urokinase inhibitors were, identified that contain a 2-aminobenzimidazole moiety. The inhibitory, potency of this family of inhibitors is similar to that of inhibitors, containing a guanidine or amidine group. However, unlike previously, described guanidino- or amidino-based inhibitors which have pK(a) values, greater than 9.0, urokinase inhibitors containing a 2-aminobenzimidazole, have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved, pharmacokinetic properties which could increase the bioavailability of, inhibitors which contain this moiety. A crystal structure of one of the, lead inhibitors, 2-amino-5-hydroxybenzimidazole, complexed with urokinase, reveals the electrostatic and hydrophobic interactions that stabilize, complex formation and suggests nearby subsites that may be accessed to, increase the potency of this new series of urokinase inhibitors.
<StructureSection load='1fv9' size='340' side='right'caption='[[1fv9]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1fv9]] is a 1 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=1FV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FV9 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]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=172:2-AMINO-5-HYDROXY-BENZIMIDAZOLE'>172</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1fv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fv9 OCA], [https://pdbe.org/1fv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fv9 RCSB], [https://www.ebi.ac.uk/pdbsum/1fv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fv9 ProSAT]</span></td></tr>
</table>
== 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 ==
[https://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fv/1fv9_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1fv9 ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known disease associated with this structure: Alzheimer disease, late-onset, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191840 191840]]
*[[Urokinase 3D Structures|Urokinase 3D Structures]]
 
== References ==
==About this Structure==
<references/>
1FV9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and 172 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.73 3.4.21.73] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1FV9 OCA].
__TOC__
 
</StructureSection>
==Reference==
Identification of novel inhibitors of urokinase via NMR-based screening., Hajduk PJ, Boyd S, Nettesheim D, Nienaber V, Severin J, Smith R, Davidson D, Rockway T, Fesik SW, J Med Chem. 2000 Oct 19;43(21):3862-6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11052791 11052791]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: U-plasminogen activator]]
[[Category: Nienaber V]]
[[Category: Nienaber, V.]]
[[Category: 172]]
[[Category: SO4]]
[[Category: plasminogen activation]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:57:40 2007''

Latest revision as of 14:16, 27 March 2024

Crystal structure of human microurokinase in complex with 2-amino-5-hydroxy-benzimidazoleCrystal structure of human microurokinase in complex with 2-amino-5-hydroxy-benzimidazole

Structural highlights

1fv9 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:,
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.

See Also

References

  1. ↑ 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

1fv9, resolution 3.00Å

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