2x6v

From Proteopedia

(Difference between revisions)

Revision as of 10:25, 20 December 2023

Crystal structure of human TBX5 in the DNA-bound and DNA-free form

Structural highlights

2x6v is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TBX5_HUMAN Holt-Oram syndrome. The disease is caused by mutations affecting the gene represented in this entry. Defects in TBX5 are associated with susceptibility to dilated cardiomyopathy (DCM). A disorder characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death.^[1] ^[2]

Function

TBX5_HUMAN DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.^[3] ^[4] ^[5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

TBX5, a member of the T-box transcription factor family, plays an important role in heart and limb development. More than 60 single point or deletion mutations of human TBX5 are associated with Holt-Oram syndrome that manifests itself as heart and limb malformations in 1 out of 100,000 live births. The majority of these mutations are located in the TBX5 T-box domain. We solved the crystal structures of the human TBX5 T-box domain in its DNA-unbound form and in complex with a natural DNA target site allowing for the first time the comparison between unbound and DNA-bound forms. Our analysis identifies a 3(10)-helix at the C-terminus of the T-box domain as an inducible recognition element, critically required for the interaction with DNA, as it only forms upon DNA binding and is unstructured in the DNA-unbound form. Using circular dichroism, we characterized the thermal stability of six TBX5 mutants containing single point mutations in the T-box domain (M74V, G80R, W121G, G169R, T223M, and R237W) and compared them with wild-type protein. Mutants G80R and W121G show drastically reduced thermal stability, while the other mutants only show a marginal stability decrease. For all TBX5 mutants, binding affinities to specific and nonspecific DNA sequences were determined using isothermal titration calorimetry. All TBX5 mutants show reduced binding affinities to a specific DNA target site, although to various degrees. Interestingly, all tested TBX5 mutants differ in their ability to bind unspecific DNA, indicating that both sequence-specific and unspecific binding might contribute to the misregulation of target gene expression.

Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form.,Stirnimann CU, Ptchelkine D, Grimm C, Muller CW J Mol Biol. 2010 Jul 2;400(1):71-81. Epub 2010 May 5. PMID:20450920^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhang XL, Qiu XB, Yuan F, Wang J, Zhao CM, Li RG, Xu L, Xu YJ, Shi HY, Hou XM, Qu XK, Xu YW, Yang YQ. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun. 2015 Mar 27;459(1):166-71. doi:, 10.1016/j.bbrc.2015.02.094. Epub 2015 Feb 26. PMID:25725155 doi:http://dx.doi.org/10.1016/j.bbrc.2015.02.094
↑ Zhou W, Zhao L, Jiang JQ, Jiang WF, Yang YQ, Qiu XB. A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. Int J Mol Med. 2015 Jul;36(1):282-8. doi: 10.3892/ijmm.2015.2206. Epub 2015 May, 11. PMID:25963046 doi:http://dx.doi.org/10.3892/ijmm.2015.2206
↑ Zhang XL, Qiu XB, Yuan F, Wang J, Zhao CM, Li RG, Xu L, Xu YJ, Shi HY, Hou XM, Qu XK, Xu YW, Yang YQ. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun. 2015 Mar 27;459(1):166-71. doi:, 10.1016/j.bbrc.2015.02.094. Epub 2015 Feb 26. PMID:25725155 doi:http://dx.doi.org/10.1016/j.bbrc.2015.02.094
↑ Zhou W, Zhao L, Jiang JQ, Jiang WF, Yang YQ, Qiu XB. A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. Int J Mol Med. 2015 Jul;36(1):282-8. doi: 10.3892/ijmm.2015.2206. Epub 2015 May, 11. PMID:25963046 doi:http://dx.doi.org/10.3892/ijmm.2015.2206
↑ Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997 Jan;15(1):21-9. PMID:8988164 doi:http://dx.doi.org/10.1038/ng0197-21
↑ Stirnimann CU, Ptchelkine D, Grimm C, Muller CW. Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form. J Mol Biol. 2010 Jul 2;400(1):71-81. Epub 2010 May 5. PMID:20450920 doi:10.1016/j.jmb.2010.04.052

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2x6v"

@@ Line 3: / Line 3: @@
 <StructureSection load='2x6v' size='340' side='right'caption='[[2x6v]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2x6v]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2X6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X6V FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2x6v]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2X6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X6V FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2x6u|2x6u]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</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=2x6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x6v OCA], [https://pdbe.org/2x6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x6v RCSB], [https://www.ebi.ac.uk/pdbsum/2x6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x6v ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/TBX5_HUMAN TBX5_HUMAN] Holt-Oram syndrome. The disease is caused by mutations affecting the gene represented in this entry.  Defects in TBX5 are associated with susceptibility to dilated cardiomyopathy (DCM). A disorder characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death.<ref>PMID:25725155</ref> <ref>PMID:25963046</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/TBX5_HUMAN TBX5_HUMAN] DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.<ref>PMID:25725155</ref> <ref>PMID:25963046</ref> <ref>PMID:8988164</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 34: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Grimm, C]]
+[[Category: Synthetic construct]]
-[[Category: Mueller, C W]]
+[[Category: Grimm C]]
-[[Category: Ptchelkine, D]]
+[[Category: Mueller CW]]
-[[Category: Stirnimann, C U]]
+[[Category: Ptchelkine D]]
-[[Category: Developmental protein]]
+[[Category: Stirnimann CU]]
-[[Category: Dna-binding]]
-[[Category: Holt-oram-syndrome]]
-[[Category: Nuclear protein]]
-[[Category: Repressor]]
-[[Category: Transcription]]
-[[Category: Transcription regulation]]
-[[Category: Transcription-dna complex]]

2x6v

From Proteopedia

Revision as of 10:25, 20 December 2023

Crystal structure of human TBX5 in the DNA-bound and DNA-free form

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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