2cn0: Difference between revisions

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-{{Seed}}
-[[Image:2cn0.png|left|200px]]
-<!--
+==Complex of Recombinant Human Thrombin with a Designed Inhibitor==
-The line below this paragraph, containing "STRUCTURE_2cn0", creates the "Structure Box" on the page.
+<StructureSection load='2cn0' size='340' side='right'caption='[[2cn0]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2cn0]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CN0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CN0 FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=F25:4-(1R,3AS,4R,8AS,8BR)-[1-DIFLUOROMETHYL-2-(4-FLUOROBENZYL)-3-OXODECAHYDROPYRROLO[3,4-A]PYRROLIZIN-4-YL]BENZAMIDINE'>F25</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene></td></tr>
-{{STRUCTURE_2cn0|  PDB=2cn0  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2cn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cn0 OCA], [https://pdbe.org/2cn0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cn0 RCSB], [https://www.ebi.ac.uk/pdbsum/2cn0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cn0 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:[https://omim.org/entry/613679 613679]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.<ref>PMID:14962227</ref> <ref>PMID:6405779</ref> <ref>PMID:3771562</ref> <ref>PMID:3567158</ref> <ref>PMID:3801671</ref> <ref>PMID:3242619</ref> <ref>PMID:2719946</ref> <ref>PMID:1354985</ref> <ref>PMID:1421398</ref> <ref>PMID:1349838</ref> <ref>PMID:7865694</ref> <ref>PMID:7792730</ref>   Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:[https://omim.org/entry/601367 601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.<ref>PMID:15534175</ref>   Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:[https://omim.org/entry/188050 188050]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis.  Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:[https://omim.org/entry/614390 614390]. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.<ref>PMID:11506076</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.<ref>PMID:2856554</ref>
+== 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/cn/2cn0_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=2cn0 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the "upper" carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K(i) values) in the range of 0.008-0.163 microM. The X-ray crystal structure of a protein-ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors.
-===COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR===
+Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket.,Hoffmann-Roder A, Schweizer E, Egger J, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F ChemMedChem. 2006 Nov;1(11):1205-15. PMID:17001711<ref>PMID:17001711</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2cn0" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_17001711}}, adds the Publication Abstract to the page
+*[[Hirudin 3D structures|Hirudin 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 17001711 is the PubMed ID number.
+*[[Thrombin 3D Structures|Thrombin 3D Structures]]
--->
+== References ==
-{{ABSTRACT_PUBMED_17001711}}
+<references/>
+__TOC__
-==About this Structure==
+</StructureSection>
-CN0 is a 3 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CN0 OCA].
+[[Category: Hirudo medicinalis]]
-==Reference==
-<ref group="xtra">PMID:17001711</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Thrombin]]
+[[Category: Large Structures]]
-[[Category: Banner, D W.]]
+[[Category: Banner DW]]
-[[Category: Diederich, F.]]
+[[Category: Diederich F]]
-[[Category: Egger, J.]]
+[[Category: Egger J]]
-[[Category: Hoffmann-Roder, A.]]
+[[Category: Hoffmann-Roder A]]
-[[Category: Kansy, M.]]
+[[Category: Kansy M]]
-[[Category: Obst-Sander, U.]]
+[[Category: Obst-Sander U]]
-[[Category: Schweizer, E.]]
+[[Category: Schweizer E]]
-[[Category: Seiler, P.]]
+[[Category: Seiler P]]
-[[Category: Wagner, B.]]
+[[Category: Wagner B]]
-[[Category: Acute phase]]
-[[Category: Blood coagulation]]
-[[Category: Calcium-binding]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Serine protease]]
-[[Category: Serine protease inhibitor complex]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Feb 16 16:42:28 2009''