2r2m

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{{Seed}}
 
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[[Image:2r2m.png|left|200px]]
 
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==2-(2-Chloro-6-Fluorophenyl)Acetamides as Potent Thrombin Inhibitors==
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The line below this paragraph, containing "STRUCTURE_2r2m", creates the "Structure Box" on the page.
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<StructureSection load='2r2m' size='340' side='right'caption='[[2r2m]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2r2m]] 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=2R2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2R2M FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I50:N-[2-({[AMINO(IMINO)METHYL]AMINO}OXY)ETHYL]-2-{6-CHLORO-3-[(2,2-DIFLUORO-2-PHENYLETHYL)AMINO]-2-FLUOROPHENYL}ACETAMIDE'>I50</scene></td></tr>
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{{STRUCTURE_2r2m| PDB=2r2m | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2r2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r2m OCA], [https://pdbe.org/2r2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2r2m RCSB], [https://www.ebi.ac.uk/pdbsum/2r2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2r2m ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r2/2r2m_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2r2m ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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2-(2-Chloro-6-fluorophenyl)acetamides having 2,2-difluoro-2-aryl/heteroaryl-ethylamine P3 and oxyguanidine P1 substituents are potent thrombin inhibitors (K(i)=0.9-33.9 nM). 2-(5-Chloro-pyridin-2-yl)-2,2-difluoroethylamine was the best P3 substituent, yielding the most potent inhibitor (K(i)=0.7 nM). Replacing the P3 heteroaryl group with a phenyl ring or replacing the difluoro substitution with dimethyl or cyclopropyl groups in the linker reduced the affinity for thrombin significantly. The aminopyridine P1s also provided an increase in potency.
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===2-(2-Chloro-6-Fluorophenyl)Acetamides as Potent Thrombin Inhibitors===
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2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors.,Lee L, Kreutter KD, Pan W, Crysler C, Spurlino J, Player MR, Tomczuk B, Lu T Bioorg Med Chem Lett. 2007 Nov 15;17(22):6266-9. Epub 2007 Sep 8. PMID:17889527<ref>PMID:17889527</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2r2m" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_17889527}}, adds the Publication Abstract to the page
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*[[Hirudin 3D structures|Hirudin 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 17889527 is the PubMed ID number.
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*[[Thrombin 3D Structures|Thrombin 3D Structures]]
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== References ==
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{{ABSTRACT_PUBMED_17889527}}
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<references/>
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__TOC__
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==Disease==
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</StructureSection>
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Known disease associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]]
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==About this Structure==
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2R2M is a 3 chains structure of sequences 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=2R2M OCA].
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==Reference==
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<ref group="xtra">PMID:17889527</ref><references group="xtra"/>
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[[Category: Hirudo medicinalis]]
[[Category: Hirudo medicinalis]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Thrombin]]
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[[Category: Large Structures]]
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[[Category: Spurlino, J.]]
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[[Category: Spurlino J]]
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[[Category: Acute phase]]
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[[Category: Blood coagulation]]
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[[Category: Calcium]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Disease mutation]]
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[[Category: Gamma-carboxyglutamic acid]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Kringle]]
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[[Category: Polymorphism]]
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[[Category: Protease]]
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[[Category: Protease inhibitor]]
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[[Category: Secreted]]
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[[Category: Serine protease]]
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[[Category: Serine protease inhibitor]]
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[[Category: Sulfation]]
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[[Category: Thrombin]]
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[[Category: Zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 13:32:29 2009''
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Current revision

2-(2-Chloro-6-Fluorophenyl)Acetamides as Potent Thrombin Inhibitors

PDB ID 2r2m

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