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| - | [[Image:1fge.gif|left|200px]]<br /> | |
| - | <applet load="1fge" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1fge" /> | |
| - | '''EPIDERMAL GROWTH FACTOR (EGF) SUBDOMAIN OF HUMAN THROMBOMODULIN (NMR, 14 STRUCTURES)'''<br /> | |
| | | | |
| - | ==Overview== | + | ==EPIDERMAL GROWTH FACTOR (EGF) SUBDOMAIN OF HUMAN THROMBOMODULIN (NMR, 14 STRUCTURES)== |
| - | The thrombin-bound structures of native peptide fragments from the fifth, EGF-like domain of thrombomodulin were determined by use of NMR and, transferred NOE spectroscopy. The bound peptides assume an EGF-like, structure of an antiparallel beta-sheet, a novel structural motif observed, for a bound peptide in protein-peptide complexes. There is a remarkable, structural resiliency of this structure motif manifested in its ability to, accommodate a different number of residues within the disulfide loop., Docking experiments revealed that the key contacts with thrombin are, hydrophobic interactions between the side chains of residues Ile 414 and, Ile 424 of thrombomodulin and a hydrophobic pocket on the thrombin, surface. Residues Leu 415, Phe 419, and Ile 420, which would have been, buried in intact EGF-like domains, are unfavorably exposed in the complex, of thrombin with the EGF-like thrombomodulin fragment, thus providing a, rationale for the enhancement of binding affinity upon the deletion of Ile, 420. The unique beta-sheet structures of the bound peptides are specified, by the presence of disulfide bridges in the peptides because a, corresponding linear thrombomodulin fragment folds into a sheet structure, with a different backbone topology. The different bound conformations for, the linear and the cyclized peptides indicate that side-chain interactions, within a specific environment may dictate the folding of bound peptides in, protein-peptide complexes. | + | <StructureSection load='1fge' size='340' side='right'caption='[[1fge]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1fge]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FGE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FGE FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 14 models</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=1fge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fge OCA], [https://pdbe.org/1fge PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fge RCSB], [https://www.ebi.ac.uk/pdbsum/1fge PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fge ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/TRBM_HUMAN TRBM_HUMAN] Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THPH12) [MIM:[https://omim.org/entry/614486 614486]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:7811989</ref> <ref>PMID:9198186</ref> <ref>PMID:12139752</ref> Defects in THBD are a cause of susceptibility to hemolytic uremic syndrome atypical type 6 (AHUS6) [MIM:[https://omim.org/entry/612926 612926]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19625716</ref> <ref>PMID:20513133</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TRBM_HUMAN TRBM_HUMAN] Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated. |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The thrombin-bound structures of native peptide fragments from the fifth EGF-like domain of thrombomodulin were determined by use of NMR and transferred NOE spectroscopy. The bound peptides assume an EGF-like structure of an antiparallel beta-sheet, a novel structural motif observed for a bound peptide in protein-peptide complexes. There is a remarkable structural resiliency of this structure motif manifested in its ability to accommodate a different number of residues within the disulfide loop. Docking experiments revealed that the key contacts with thrombin are hydrophobic interactions between the side chains of residues Ile 414 and Ile 424 of thrombomodulin and a hydrophobic pocket on the thrombin surface. Residues Leu 415, Phe 419, and Ile 420, which would have been buried in intact EGF-like domains, are unfavorably exposed in the complex of thrombin with the EGF-like thrombomodulin fragment, thus providing a rationale for the enhancement of binding affinity upon the deletion of Ile 420. The unique beta-sheet structures of the bound peptides are specified by the presence of disulfide bridges in the peptides because a corresponding linear thrombomodulin fragment folds into a sheet structure with a different backbone topology. The different bound conformations for the linear and the cyclized peptides indicate that side-chain interactions within a specific environment may dictate the folding of bound peptides in protein-peptide complexes. |
| | | | |
| - | ==Disease==
| + | Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin.,Hrabal R, Komives EA, Ni F Protein Sci. 1996 Feb;5(2):195-203. PMID:8745396<ref>PMID:8745396</ref> |
| - | Known diseases associated with this structure: Myocardial infarction, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188040 188040]], Thrombophilia due to thrombomodulin defect OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188040 188040]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1FGE is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1FGE OCA].
| + | </div> |
| - | | + | <div class="pdbe-citations 1fge" style="background-color:#fffaf0;"></div> |
| - | ==Reference== | + | == References == |
| - | Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin., Hrabal R, Komives EA, Ni F, Protein Sci. 1996 Feb;5(2):195-203. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=8745396 8745396]
| + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Hrabal, R.]] | + | [[Category: Hrabal R]] |
| - | [[Category: Komives, E.A.]] | + | [[Category: Komives EA]] |
| - | [[Category: Ni, F.]] | + | [[Category: Ni F]] |
| - | [[Category: blood coagulation inhibitor]]
| + | |
| - | [[Category: egf]]
| + | |
| - | [[Category: thrombomodulin]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:52:53 2007''
| + | |
| Structural highlights
Disease
TRBM_HUMAN Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THPH12) [MIM:614486. A hemostatic disorder characterized by a tendency to thrombosis.[1] [2] [3] Defects in THBD are a cause of susceptibility to hemolytic uremic syndrome atypical type 6 (AHUS6) [MIM:612926. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.[4] [5]
Function
TRBM_HUMAN Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
Publication Abstract from PubMed
The thrombin-bound structures of native peptide fragments from the fifth EGF-like domain of thrombomodulin were determined by use of NMR and transferred NOE spectroscopy. The bound peptides assume an EGF-like structure of an antiparallel beta-sheet, a novel structural motif observed for a bound peptide in protein-peptide complexes. There is a remarkable structural resiliency of this structure motif manifested in its ability to accommodate a different number of residues within the disulfide loop. Docking experiments revealed that the key contacts with thrombin are hydrophobic interactions between the side chains of residues Ile 414 and Ile 424 of thrombomodulin and a hydrophobic pocket on the thrombin surface. Residues Leu 415, Phe 419, and Ile 420, which would have been buried in intact EGF-like domains, are unfavorably exposed in the complex of thrombin with the EGF-like thrombomodulin fragment, thus providing a rationale for the enhancement of binding affinity upon the deletion of Ile 420. The unique beta-sheet structures of the bound peptides are specified by the presence of disulfide bridges in the peptides because a corresponding linear thrombomodulin fragment folds into a sheet structure with a different backbone topology. The different bound conformations for the linear and the cyclized peptides indicate that side-chain interactions within a specific environment may dictate the folding of bound peptides in protein-peptide complexes.
Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin.,Hrabal R, Komives EA, Ni F Protein Sci. 1996 Feb;5(2):195-203. PMID:8745396[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ohlin AK, Marlar RA. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood. 1995 Jan 15;85(2):330-6. PMID:7811989
- ↑ Ohlin AK, Norlund L, Marlar RA. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost. 1997 Jul;78(1):396-400. PMID:9198186
- ↑ Faioni EM, Franchi F, Castaman G, Biguzzi E, Rodeghiero F. Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Br J Haematol. 2002 Aug;118(2):595-9. PMID:12139752
- ↑ Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jul 23;361(4):345-57. doi: 10.1056/NEJMoa0810739. PMID:19625716 doi:10.1056/NEJMoa0810739
- ↑ Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. PMID:20513133 doi:10.1002/humu.21256
- ↑ Hrabal R, Komives EA, Ni F. Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin. Protein Sci. 1996 Feb;5(2):195-203. PMID:8745396
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