2x6v

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

spinqualitylabelsall models 2x6v, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: MG, PE4 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. Function TBX5_HUMAN DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also T-box proteins

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