5k8d: Difference between revisions

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-'''Unreleased structure'''
-The entry 5k8d is ON HOLD  until Paper Publication
+==Crystal structure of rFVIIIFc==
+<StructureSection load='5k8d' size='340' side='right'caption='[[5k8d]], [[Resolution|resolution]] 4.19&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5k8d]] 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=5K8D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K8D 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]] 4.19&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CU:COPPER+(II)+ION'>CU</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=5k8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k8d OCA], [https://pdbe.org/5k8d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k8d RCSB], [https://www.ebi.ac.uk/pdbsum/5k8d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k8d ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/FA8_HUMAN FA8_HUMAN] Defects in F8 are the cause of hemophilia A (HEMA) [MIM:[https://omim.org/entry/306700 306700]. A disorder of blood coagulation characterized by a permanent tendency to hemorrhage. About 50% of patients have severe hemophilia resulting in frequent spontaneous bleeding into joints, muscles and internal organs. Less severe forms are characterized by bleeding after trauma or surgery. Note=Of particular interest for the understanding of the function of F8 is the category of CRM (cross-reacting material) positive patients (approximately 5%) that have considerable amount of F8 in their plasma (at least 30% of normal), but the protein is non-functional; i.e. the F8 activity is much less than the plasma protein level. CRM-reduced is another category of patients in which the F8C antigen and activity are reduced to approximately the same level. Most mutations are CRM negative, and probably affect the folding and stability of the protein.<ref>PMID:3012775</ref> <ref>PMID:3122181</ref> <ref>PMID:2833855</ref> <ref>PMID:2835904</ref> <ref>PMID:2499363</ref> <ref>PMID:2506948</ref> <ref>PMID:2510835</ref> <ref>PMID:2495245</ref> <ref>PMID:2498882</ref> <ref>PMID:2104766</ref> <ref>PMID:2105106</ref> <ref>PMID:1973901</ref> <ref>PMID:2105906</ref> <ref>PMID:2106480</ref> <ref>PMID:2107542</ref> <ref>PMID:1908817</ref> <ref>PMID:1908096</ref> <ref>PMID:1851341</ref> <ref>PMID:1356412</ref> <ref>PMID:1639429</ref> <ref>PMID:1349567</ref> <ref>PMID:1301194</ref> <ref>PMID:1301932</ref> <ref>PMID:1301960</ref> <ref>PMID:8449505</ref> <ref>PMID:8322269</ref> <ref>PMID:7579394</ref> <ref>PMID:7794769</ref> <ref>PMID:7759074</ref> <ref>PMID:8644728</ref> <ref>PMID:8639447</ref> <ref>PMID:8759905</ref> <ref>PMID:9029040</ref> <ref>PMID:9326186</ref> <ref>PMID:9341862</ref> <ref>PMID:9886318</ref> <ref>PMID:9450898</ref> <ref>PMID:10215414</ref> <ref>PMID:9603440</ref> <ref>PMID:9452104</ref> <ref>PMID:9792405</ref> <ref>PMID:9829908</ref> <ref>PMID:9569180</ref> <ref>PMID:9569189</ref> <ref>PMID:10554831</ref> <ref>PMID:10338101</ref> <ref>PMID:10408784</ref> <ref>PMID:10404764</ref> <ref>PMID:10910910</ref> <ref>PMID:10910913</ref> <ref>PMID:10691849</ref> <ref>PMID:10886198</ref> <ref>PMID:10800171</ref> <ref>PMID:10896236</ref> <ref>PMID:10612839</ref> <ref>PMID:11410838</ref> <ref>PMID:11298607</ref> <ref>PMID:11442643</ref> <ref>PMID:11442647</ref> <ref>PMID:11554935</ref> <ref>PMID:11748850</ref> <ref>PMID:11341489</ref> <ref>PMID:12351418</ref> <ref>PMID:12406074</ref> <ref>PMID:12199686</ref> <ref>PMID:11857744</ref> <ref>PMID:12203998</ref> <ref>PMID:12325022</ref> <ref>PMID:11858487</ref> <ref>PMID:12195713</ref> <ref>PMID:12930394</ref> <ref>PMID:12871415</ref> <ref>PMID:12614369</ref> <ref>PMID:15682412</ref> <ref>PMID:15810915</ref> <ref>PMID:16805874</ref> <ref>PMID:18184865</ref> <ref>PMID:21371196</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/FA8_HUMAN FA8_HUMAN] Factor VIII, along with calcium and phospholipid, acts as a cofactor for factor IXa when it converts factor X to the activated form, factor Xa.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Essentials Recombinant factor VIII (rFVIII) Fc fusion protein has a 1.5-fold longer half-life than rFVIII. Five orthogonal methods were used to characterize the structure of rFVIIIFc compared to rFVIII. The C-terminal Fc fusion does not perturb the structure of FVIII in rFVIIIFc. The FVIII and Fc components of rFVIIIFc are flexibly tethered and functionally independent. SUMMARY: Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.
-Authors:
+The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein.,Leksa NC, Chiu PL, Bou-Assaf GM, Quan C, Liu Z, Goodman AB, Chambers MG, Tsutakawa SE, Hammel M, Peters RT, Walz T, Kulman JD J Thromb Haemost. 2017 Jun;15(6):1167-1179. doi: 10.1111/jth.13700. Epub 2017 May, 3. PMID:28397397<ref>PMID:28397397</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5k8d" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Factor VIII|Factor VIII]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Leksa N]]
+[[Category: Quan C]]