3f6u

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[[Image:3f6u.png|left|200px]]
 
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==Crystal structure of human Activated Protein C (APC) complexed with PPACK==
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The line below this paragraph, containing "STRUCTURE_3f6u", creates the "Structure Box" on the page.
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<StructureSection load='3f6u' size='340' side='right'caption='[[3f6u]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
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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'>[[3f6u]] is a 2 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=3F6U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3F6U FirstGlance]. <br>
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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]] 2.8&#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=0G6:D-PHENYLALANYL-N-[(2S,3S)-6-{[AMINO(IMINIO)METHYL]AMINO}-1-CHLORO-2-HYDROXYHEXAN-3-YL]-L-PROLINAMIDE'>0G6</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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{{STRUCTURE_3f6u| PDB=3f6u | 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=3f6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f6u OCA], [https://pdbe.org/3f6u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3f6u RCSB], [https://www.ebi.ac.uk/pdbsum/3f6u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3f6u ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PROC_HUMAN PROC_HUMAN] Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:[https://omim.org/entry/176860 176860]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency.<ref>PMID:8560401</ref> <ref>PMID:2437584</ref> <ref>PMID:2602169</ref> <ref>PMID:1868249</ref> <ref>PMID:1347706</ref> <ref>PMID:1511989</ref> <ref>PMID:1301959</ref> <ref>PMID:8499568</ref> <ref>PMID:8292730</ref> <ref>PMID:8398832</ref> <ref>PMID:7865674</ref> <ref>PMID:7792728</ref> <ref>PMID:8829639</ref> <ref>PMID:9798967</ref> Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:[https://omim.org/entry/612304 612304]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare.
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== Function ==
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[https://www.uniprot.org/uniprot/PROC_HUMAN PROC_HUMAN] Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.
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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/f6/3f6u_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=3f6u 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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The serine protease domain of activated protein C (APC) contains a Na+ and a Ca2+ site. However, the number and identity of the APC residues that coordinate to Na+ is not precisely known. Further, the functional link between the Na+ and the Ca2+ site is insufficiently defined, and their linkage to the substrate S1 site has not been studied. Here, we systematically investigate the functional significance of these two cation sites and their thermodynamic links to the S1 site. Kinetic data reveal that Na+ binds to the substrate-occupied APC with K(d) values of approximately 24 mm in the absence and approximately 6 mm in the presence of Ca2+. Sodium-occupied APC has approximately 100-fold increased catalytic efficiency ( approximately 4-fold decrease in K(m) and approximately 25-fold increase in k(cat)) in hydrolyzing S-2288 (H-d-Ile-Pro-Arg-p-nitroanilide) and Ca2+ further increases this k(cat) slightly ( approximately 1.2-fold). Ca2+ binds to the protease domain of APC with K(d) values of approximately 438 microm in the absence and approximately 105 microm in the presence of Na+. Ca2+ binding to the protease domain of APC does not affect K(m) but increases the k(cat) approximately 10-fold, and Na+ further increases this k(cat) approximately 3-fold and decreases the K(m) value approximately 3.7-fold. In agreement with the K(m) data, sodium-occupied APC has approximately 4-fold increased affinity in binding to p-aminobenzamidine (S1 probe). Crystallographically, the Ca2+ site in APC is similar to that in trypsin, and the Na+ site is similar to that in factor Xa but not thrombin. Collectively, the Na+ site is thermodynamically linked to the S1 site as well as to the protease domain Ca2+ site, whereas the Ca2+ site is only linked to the Na+ site. The significance of these findings is that under physiologic conditions, most of the APC will exist in Na2+-APC-Ca2+ form, which has 110-fold increased proteolytic activity.
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===Crystal structure of human Activated Protein C (APC) complexed with PPACK===
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Thermodynamic linkage between the S1 site, the Na+ site, and the Ca2+ site in the protease domain of human activated protein C (APC). Sodium ion in the APC crystal structure is coordinated to four carbonyl groups from two separate loops.,Schmidt AE, Padmanabhan K, Underwood MC, Bode W, Mather T, Bajaj SP J Biol Chem. 2002 Aug 9;277(32):28987-95. Epub 2002 May 23. PMID:12029084<ref>PMID:12029084</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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The line below this paragraph, {{ABSTRACT_PUBMED_9003757}}, adds the Publication Abstract to the page
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<div class="pdbe-citations 3f6u" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 9003757 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_9003757}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[3f6u]] is a 2 chain structure with sequence 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=3F6U OCA].
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==Reference==
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<ref group="xtra">PMID:009003757</ref><ref group="xtra">PMID:012029084</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bajaj, S P.]]
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[[Category: Large Structures]]
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[[Category: Bode, W.]]
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[[Category: Bajaj SP]]
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[[Category: Mather, T.]]
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[[Category: Bode W]]
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[[Category: Padmanabhan, K.]]
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[[Category: Mather T]]
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[[Category: Schmidt, A E.]]
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[[Category: Padmanabhan K]]
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[[Category: Underwood, M C.]]
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[[Category: Schmidt AE]]
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[[Category: Blood coagulation]]
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[[Category: Underwood MC]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Serine protease]]
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Current revision

Crystal structure of human Activated Protein C (APC) complexed with PPACK

PDB ID 3f6u

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