View source for 1nro


==CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES==
<StructureSection load='1nro' size='340' side='right'caption='[[1nro]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1nro]] is a 3 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=1NRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NRO 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]] 3.1&#8491;</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=1nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nro OCA], [https://pdbe.org/1nro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nro RCSB], [https://www.ebi.ac.uk/pdbsum/1nro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nro 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/nr/1nro_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=1nro ConSurf].
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== Publication Abstract from PubMed ==
Many of the vital actions of thrombin on platelets and other cells appear to be mediated by the recently cloned seven-transmembrane-domain thrombin receptor. Thrombin activates this receptor by a novel proteolytic mechanism. The amino-terminal exodomain of the receptor contains the sequence LDPRSFLLRNPNDKYEPF. Structure-activity studies with mutant receptors and receptor peptides suggest that this sequence binds to thrombin at two sites: LDPR with the active center of thrombin and KYEPF with the fibrinogen recognition exosite of thrombin. Thrombin then cleaves the Arg41-Ser42 bond to unmask a new amino terminus, which functions as a tethered peptide ligand binding to as yet undefined sites within the body of the receptor to effect receptor activation. We have determined eight crystal structures of thrombin complexed with receptor-based peptides. Each of the two components of the bidentate docking model was captured in individual cocrystals. In one crystal type, the LDPR sequence docked in the active center of thrombin in a manner analogous to d-PheProArg chloromethyl ketone. In other crystals, the KYEPF sequence bound in the fibrinogen anion binding exosite of thrombin in a manner analogous to the DFEEI sequence of the carboxylate-terminal peptide of hirudin. Strikingly, however, generation of a single crystal that includes both components of the anticipated bidentate binding mode was not achieved, apparently because the peptides have a dominant solution S-like conformation that does not bind in a productive way at the active center. This peptide structure apparently favored a novel alternative mode of receptor peptide-thrombin interaction in which the receptor peptides formed an intermolecular bridge between neighboring thrombin molecules, resulting in an infinite peptide thrombin chain in crystals. In this structure, the KYEPF sequence docked in the expected manner at the exosite of one thrombin molecule, but the LDPR sequence docked in an unusual nonproductive mode with the active center of a neighboring molecule. Mutations that removed important determinants of the S-like receptor peptide structure underlying the bridging mode in the receptor itself did not significantly alter thrombin signaling. Additionally, a comparison of receptor density to the responsiveness of a cell did not support a role for receptor oligomerization in signaling. The physiological role for this unexpected intermolecular binding mode, if any, remains to be identified.(ABSTRACT TRUNCATED AT 400 WORDS)

Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes.,Mathews II, Padmanabhan KP, Ganesh V, Tulinsky A, Ishii M, Chen J, Turck CW, Coughlin SR, Fenton JW 2nd Biochemistry. 1994 Mar 22;33(11):3266-79. PMID:8136362<ref>PMID:8136362</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1nro" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thrombin 3D Structures|Thrombin 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mathews II]]
[[Category: Tulinsky A]]