2c93: Difference between revisions

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-[[Image:2c93.png|left|200px]]
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+==thrombin inhibitors==
-The line below this paragraph, containing "STRUCTURE_2c93", creates the "Structure Box" on the page.
+<StructureSection load='2c93' size='340' side='right'caption='[[2c93]], [[Resolution|resolution]] 2.20&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'>[[2c93]] 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=2C93 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C93 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]] 2.2&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C4M:N-[(2R,3S)-3-AMINO-2-HYDROXY-4-PHENYLBUTYL]-4-METHOXY-2,3,6-TRIMETHYLBENZENESULFONAMIDE'>C4M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr>
-{{STRUCTURE_2c93|  PDB=2c93  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2c93 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c93 OCA], [https://pdbe.org/2c93 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c93 RCSB], [https://www.ebi.ac.uk/pdbsum/2c93 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c93 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/c9/2c93_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2c93 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture.
-===THROMBIN INHIBITORS===
+Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors.,Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL J Med Chem. 2006 Feb 23;49(4):1346-55. PMID:16480269<ref>PMID:16480269</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<!--
+</div>
-The line below this paragraph, {{ABSTRACT_PUBMED_16480269}}, adds the Publication Abstract to the page
+<div class="pdbe-citations 2c93" style="background-color:#fffaf0;"></div>
-(as it appears on PubMed at http://www.pubmed.gov), where 16480269 is the PubMed ID number.
--->
-{{ABSTRACT_PUBMED_16480269}}
-==About this Structure==
-[[2c93]] is a 3 chain structure of [[Hirudin]] with sequence from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C93 OCA].
 ==See Also==
-*[[Hirudin]]
+*[[Hirudin 3D structures|Hirudin 3D structures]]
+*[[Thrombin 3D Structures|Thrombin 3D Structures]]
-==Reference==
+== References ==
-<ref group="xtra">PMID:16480269</ref><references group="xtra"/>
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Hirudo medicinalis]]
 [[Category: Homo sapiens]]
-[[Category: Thrombin]]
+[[Category: Large Structures]]
-[[Category: Abell, C.]]
+[[Category: Abell C]]
-[[Category: Blakemore, W.]]
+[[Category: Blakemore W]]
-[[Category: Carr, R.]]
+[[Category: Carr R]]
-[[Category: Chessari, G.]]
+[[Category: Chessari G]]
-[[Category: Congreve, M.]]
+[[Category: Congreve M]]
-[[Category: Howard, N.]]
+[[Category: Howard N]]
-[[Category: Howard, S.]]
+[[Category: Howard S]]
-[[Category: Jhoti, H.]]
+[[Category: Jhoti H]]
-[[Category: Montfort, R L.M Van.]]
+[[Category: Murray CW]]
-[[Category: Murray, C W.]]
+[[Category: Seavers LCA]]
-[[Category: Seavers, L C.A.]]
+[[Category: Van Montfort RLM]]
-[[Category: Blood coagulation]]
-[[Category: Gamma-carboxyglutamic acid]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Kringle]]
-[[Category: Protease]]
-[[Category: Serine protease]]
-[[Category: Thrombin]]