5vln
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==NMR structure of the N-domain of troponin C bound to switch region of troponin I== | |
| + | <StructureSection load='5vln' size='340' side='right' caption='[[5vln]], [[NMR_Ensembles_of_Models | 8 NMR models]]' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5vln]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VLN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VLN FirstGlance]. <br> | ||
| + | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5vl6|5vl6]]</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=5vln FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vln OCA], [http://pdbe.org/5vln PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vln RCSB], [http://www.ebi.ac.uk/pdbsum/5vln PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vln ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/TNNC1_HUMAN TNNC1_HUMAN]] Defects in TNNC1 are the cause of cardiomyopathy dilated type 1Z (CMD1Z) [MIM:[http://omim.org/entry/611879 611879]]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:15542288</ref> Defects in TNNC1 are the cause of familial hypertrophic cardiomyopathy type 13 (CMH13) [MIM:[http://omim.org/entry/613243 613243]]. A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.<ref>PMID:11385718</ref> <ref>PMID:16302972</ref> <ref>PMID:18572189</ref> <ref>PMID:19439414</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/TNNC1_HUMAN TNNC1_HUMAN]] Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | In cardiac and skeletal muscle, the troponin complex turns muscle contraction on and off in a calcium-dependent manner. Many small molecules are known to bind to the troponin complex to modulate its calcium binding affinity, and this may be useful in a broad range of conditions in which striated muscle function is compromised, such as congestive heart failure. As a tool for developing drugs specific for the cardiac isoform of troponin, we have designed a chimeric construct (cChimera) consisting of the regulatory N-terminal domain of cardiac troponin C (cNTnC) fused to the switch region of cardiac troponin I (cTnI), mimicking the key binding event that turns on muscle contraction. We demonstrate by solution NMR spectroscopy that cChimera faithfully reproduces the native interface between cTnI and cNTnC. We determined that small molecules based on diphenylamine can bind to cChimera with a KD as low as 10muM. Solution NMR structures show that minimal structural perturbations in cChimera are needed to accommodate 3-methyldiphenylamine (3-mDPA), which is probably why it binds with higher affinity than previously studied compounds like bepridil, despite its significantly smaller size. The unsubstituted aromatic ring of 3-mDPA binds to an inner hydrophobic pocket adjacent to the central beta sheet of cNTnC. However, the methyl-substituted ring is able to bind in two different orientations, either inserting into the cNTnC-cTnI interface or "flipping out" to form contacts primarily with helix C of cNTnC. Our work suggests that preservation of the native interaction between cNTnC and cTnI is key to the development of a high affinity cardiac troponin-specific drug. | ||
| - | + | Structures reveal details of small molecule binding to cardiac troponin.,Cai F, Li MX, Pineda-Sanabria SE, Gelozia S, Lindert S, West F, Sykes BD, Hwang PM J Mol Cell Cardiol. 2016 Dec;101:134-144. doi: 10.1016/j.yjmcc.2016.10.016. Epub , 2016 Nov 5. PMID:27825981<ref>PMID:27825981</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5vln" style="background-color:#fffaf0;"></div> | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Cai, F]] | [[Category: Cai, F]] | ||
| - | [[Category: Hwang, P | + | [[Category: Hwang, P M]] |
| + | [[Category: Sykes, B D]] | ||
| + | [[Category: Cardiac troponin calcium binding protein ef hand]] | ||
| + | [[Category: Cell invasion]] | ||
| + | [[Category: Metal binding protein]] | ||
Revision as of 13:35, 24 May 2017
NMR structure of the N-domain of troponin C bound to switch region of troponin I
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