2puq

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
(New page: 200px<br /> <applet load="2puq" size="450" color="white" frame="true" align="right" spinBox="true" caption="2puq, resolution 2.050&Aring;" /> '''Crystal structure ...)
Current revision (11:09, 30 August 2023) (edit) (undo)
 
(21 intermediate revisions not shown.)
Line 1: Line 1:
-
[[Image:2puq.gif|left|200px]]<br />
 
-
<applet load="2puq" size="450" color="white" frame="true" align="right" spinBox="true"
 
-
caption="2puq, resolution 2.050&Aring;" />
 
-
'''Crystal structure of active site inhibited coagulation factor VIIA in complex with soluble tissue factor'''<br />
 
-
==Overview==
+
==Crystal structure of active site inhibited coagulation factor VIIA in complex with soluble tissue factor==
-
The remarkably high specificity of the coagulation proteases towards, macromolecular substrates is provided by numerous interactions involving, the catalytic groove and remote exosites. For factor VIIa (FVIIa), the, principal initiator of coagulation via the extrinsic pathway, several, exosites have been identified, whereas only little is known about the, specificity dictated by the active-site architecture. Here, we have, profiled the primary P4-P1 substrate specificity of FVIIa using positional, scanning-substrate combinatorial libraries and evaluated the role of, selective active site in defining specificity. Being a trypsin-like serine, protease, FVIIa showed P1 specificity exclusively towards Arg and Lys. In, the S2 pocket Thr, Leu, Phe and Val were the most preferred amino acids., Both S3 and S4 appeared to be rather promiscuous, however, with some, preference for aromatic amino acids at both positions. Interestingly, a, significant degree of interdependence between the S3 and S4 was observed, and as a consequence, the optimal substrate for FVIIa could not be derived, directly from a sub-site directed specificity screen. To evaluate the role, of the active site residues in defining specificity, a series of mutants, of FVIIa were prepared at position 239 (c99), which is considered one of, the most important residues for determining P2 specificity of the trypsin, family members. This was confirmed for FVIIa by marked changes in primary, substrate specificity and reduced rates of antithrombin III inhibition., Interestingly, these changes do not necessarily coincide with an altered, ability to activate factor X demonstrating that inhibitor and, macromolecular substrate selectivity may be engineered separately.
+
<StructureSection load='2puq' size='340' side='right'caption='[[2puq]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[2puq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2pmm 2pmm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PUQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PUQ 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]] 2.05&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=AR7:AMINO{[(4S)-4-AMINO-5,5-DIHYDROXYPENTYL]AMINO}METHANIMINIUM'>AR7</scene>, <scene name='pdbligand=BGC:BETA-D-GLUCOSE'>BGC</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</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=2puq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2puq OCA], [https://pdbe.org/2puq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2puq RCSB], [https://www.ebi.ac.uk/pdbsum/2puq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2puq ProSAT]</span></td></tr>
 +
</table>
 +
== Disease ==
 +
[https://www.uniprot.org/uniprot/FA7_HUMAN FA7_HUMAN] Defects in F7 are the cause of factor VII deficiency (FA7D) [MIM:[https://omim.org/entry/227500 227500]. A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels.<ref>PMID:8043443</ref> <ref>PMID:2070047</ref> <ref>PMID:1634227</ref> <ref>PMID:8364544</ref> <ref>PMID:8204879</ref> <ref>PMID:7981691</ref> <ref>PMID:7974346</ref> <ref>PMID:8652821</ref> <ref>PMID:8844208</ref> <ref>PMID:8940045</ref> <ref>PMID:8883260</ref> <ref>PMID:9414278</ref> <ref>PMID:9576180</ref> <ref>PMID:9452082</ref> <ref>PMID:11091194</ref> <ref>PMID:11129332</ref> <ref>PMID:10862079</ref> <ref>PMID:12472587</ref> <ref>PMID:14717781</ref> <ref>PMID:19751712</ref> <ref>PMID:18976247</ref> <ref>PMID:19432927</ref> <ref>PMID:21206266</ref> <ref>PMID:21372693</ref>
 +
== Function ==
 +
[https://www.uniprot.org/uniprot/FA7_HUMAN FA7_HUMAN] Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.
 +
== 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/pu/2puq_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=2puq ConSurf].
 +
<div style="clear:both"></div>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
The remarkably high specificity of the coagulation proteases towards macromolecular substrates is provided by numerous interactions involving the catalytic groove and remote exosites. For FVIIa [activated FVII (Factor VII)], the principal initiator of coagulation via the extrinsic pathway, several exosites have been identified, whereas only little is known about the specificity dictated by the active-site architecture. In the present study, we have profiled the primary P4-P1 substrate specificity of FVIIa using positional scanning substrate combinatorial libraries and evaluated the role of the selective active site in defining specificity. Being a trypsin-like serine protease, FVIIa had P1 specificity exclusively towards arginine and lysine residues. In the S2 pocket, threonine, leucine, phenylalanine and valine residues were the most preferred amino acids. Both S3 and S4 appeared to be rather promiscuous, however, with some preference for aromatic amino acids at both positions. Interestingly, a significant degree of interdependence between the S3 and S4 was observed and, as a consequence, the optimal substrate for FVIIa could not be derived directly from a subsite-directed specificity screen. To evaluate the role of the active-site residues in defining specificity, a series of mutants of FVIIa were prepared at position 239 (position 99 in chymotrypsin), which is considered to be one of the most important residues for determining P2 specificity of the trypsin family members. This was confirmed for FVIIa by marked changes in primary substrate specificity and decreased rates of antithrombin III inhibition. Interestingly, these changes do not necessarily coincide with an altered ability to activate Factor X, demonstrating that inhibitor and macromolecular substrate selectivity may be engineered separately.
-
==Disease==
+
Engineering the substrate and inhibitor specificities of human coagulation Factor VIIa.,Larsen KS, Ostergaard H, Bjelke JR, Olsen OH, Rasmussen HB, Christensen L, Kragelund BB, Stennicke HR Biochem J. 2007 Aug 1;405(3):429-38. PMID:17456045<ref>PMID:17456045</ref>
-
Known diseases associated with this structure: Esophageal squamous cell carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606551 606551]], Factor VII deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227500 227500]], Myocardial infarction, decreased susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227500 227500]]
+
-
==About this Structure==
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
2PUQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GLC, FUC, CA and CH2 as [http://en.wikipedia.org/wiki/ligands ligands]. This structure superseeds the now removed PDB entry 2PMM. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_VIIa Coagulation factor VIIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.21 3.4.21.21] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2PUQ OCA].
+
</div>
 +
<div class="pdbe-citations 2puq" style="background-color:#fffaf0;"></div>
-
==Reference==
+
==See Also==
-
Engineering the substrate and inhibitor specificities of human coagulation factor VIIa., Larsen KS, Ostergaard H, Bjelke JR, Olsen OH, Rasmussen HB, Christensen L, Kragelund BB, Stennicke HR, Biochem J. 2007 Apr 25;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17456045 17456045]
+
*[[Factor VIIa 3D structures|Factor VIIa 3D structures]]
-
[[Category: Coagulation factor VIIa]]
+
*[[Tissue factor|Tissue factor]]
 +
== References ==
 +
<references/>
 +
__TOC__
 +
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Protein complex]]
+
[[Category: Large Structures]]
-
[[Category: Bjelke, J.R.]]
+
[[Category: Bjelke JR]]
-
[[Category: Rasmussen, H.B.]]
+
[[Category: Rasmussen HB]]
-
[[Category: CA]]
+
-
[[Category: CH2]]
+
-
[[Category: FUC]]
+
-
[[Category: GLC]]
+
-
[[Category: active site inhibitor; substrate profile]]
+
-
 
+
-
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:27:13 2007''
+

Current revision

Crystal structure of active site inhibited coagulation factor VIIA in complex with soluble tissue factor

PDB ID 2puq

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2puq"
Personal tools