This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

1egt

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 03:55, 6 September 2017

THROMBIN-BOUND STRUCTURE OF AN EGF SUBDOMAIN FROM HUMAN THROMBOMODULIN DETERMINED BY TRANSFERRED NUCLEAR OVERHAUSER EFFECTS

Structural highlights

1egt is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 EGF-like domains in human thrombomodulin interact with and change the specificity of thrombin from a procoagulant enzyme to an anticoagulant enzyme. Recent experiments identified the minimal thrombin-binding region of thrombomodulin as the most acidic loop of the fifth EGF-like domain with a sequence of E408CPEGYILDDGFI420CTDIDE. High-resolution NMR spectroscopy was employed to characterize the interaction of a des-Ile420 thrombomodulin peptide, Cys1(409)Pro2Glu3Gly4Tyr5Ile6- Leu7Asp8Asp9Gly10Phe11Cys12Thr13Asp14Ile15Asp16Glu17(426), with its target coagulation protein, thrombin. The disulfide-bonded peptide was found to be structured only upon binding, while neither the linear nor the cyclized peptide exhibited any structural preference free in solution. The thrombin-bound structure of the cyclic thrombomodulin peptide was determined by transferred nuclear Overhauser effects (transferred NOEs) and by distance geometry and Monte Carlo calculations. The thrombin-bound cyclic peptide assumes an overall conformation similar to those observed in the free but intact EGF molecules. There is a type II beta-turn involving residues Pro2-Tyr5, followed by an optimized antiparallel beta-sheet involving residues Gly4-Asp8 and residues Phe11-Ile15. The thrombomodulin peptide provides a potential thrombin-binding surface between residues Tyr5 and Phe11, which are brought close by a chain reversal within the central beta-sheet. Comparison of the thrombin-bound structure of the EGF-like subdomain with other thrombin-peptide complexes revealed that a common thrombin-binding surface can be organized by different secondary structure elements with entirely different peptide sequences. The thrombin-bound structure of the thrombomodulin peptide may serve as a basis to understand the regulatory functions of thrombomodulin and as a guide for the design of specific inhibitors for thrombin.

Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects.,Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F Biochemistry. 1994 Nov 22;33(46):13553-60. PMID:7947766^[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
↑ Srinivasan J, Hu S, Hrabal R, Zhu Y, Komives EA, Ni F. Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects. Biochemistry. 1994 Nov 22;33(46):13553-60. PMID:7947766

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1egt"

Categories: Ni, F | Blood coagulation inhibitor | Egf | Epidermal growth factor

@@ Line 1: / Line 1: @@
 ==THROMBIN-BOUND STRUCTURE OF AN EGF SUBDOMAIN FROM HUMAN THROMBOMODULIN DETERMINED BY TRANSFERRED NUCLEAR OVERHAUSER EFFECTS==
 <StructureSection load='1egt' size='340' side='right' caption='[[1egt]], [[NMR_Ensembles_of_Models | 3 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1egt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EGT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1EGT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1egt]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EGT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1EGT FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1egt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1egt OCA], [http://pdbe.org/1egt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1egt RCSB], [http://www.ebi.ac.uk/pdbsum/1egt PDBsum]</span></td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1egt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1egt OCA], [http://pdbe.org/1egt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1egt RCSB], [http://www.ebi.ac.uk/pdbsum/1egt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1egt ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
 [[Category: Ni, F]]
 [[Category: Blood coagulation inhibitor]]
 [[Category: Egf]]
 [[Category: Epidermal growth factor]]

1egt

From Proteopedia

Revision as of 03:55, 6 September 2017

THROMBIN-BOUND STRUCTURE OF AN EGF SUBDOMAIN FROM HUMAN THROMBOMODULIN DETERMINED BY TRANSFERRED NUCLEAR OVERHAUSER EFFECTS

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox