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Crystal structure of a promoter sequence in the B-raf gene reveals an intertwined dimer quadruplex

DOI: 10.1021/ja4101358 DOI Help
PMID: 24295054 PMID Help

Authors: Dengguo Wei (University College London) , Alan K. Todd (University College London) , Mire Zloh (University College London) , Mekala Gunaratnam (University College London) , Gary Parkinson (University of London) , Stephen Neidle (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society , VOL 135 (51) , PAGES 19319 - 19329

State: Published (Approved)
Published: December 2013

Abstract: The sequence d(GGGCGGGGAGGGGGAAGGGA) occurs in the promoter region of the B-raf gene. An X-ray crystallographic study has found that this forms an unprecedented dimeric quadruplex arrangement, with a core of seven consecutive G-quartets and an uninterrupted run of six potassium ions in the central channel of the quadruplex. Analogy with previously reported promoter quadruplexes had initially suggested that in common with these a monomeric quadruplex was to be expected. The structure has a distorted G·C·G·C base quartet at one end and four flipped-out adenosine nucleosides at the other. The only loops in the structure are formed by the cytosine and by the three adenosines within the sequence, with all of the guanosines participating in G-quartet formation. Solution UV and circular dichroism data are in accord with a stable quadruple arrangement being formed. 1D NMR data, together with gel electrophoresis measurements, are consistent with a dimer being the dominant species in potassium solution. A single-chain intramolecular quadruplex has been straightforwardly constructed using molecular modeling, by means of a six-nucleotide sequence joining 3′ and 5′ ends of each strand in the dimer. A human genomic database search has revealed a number of sequences containing eight or more consecutive short G-tracts, suggesting that such intramolecular quadruplexes could be formed within the human genome.

Journal Keywords: Circular; Crystallography; X-Ray; Dimerization; Electrophoresis; Agar; G-Quadruplexes; Humans; Models; Molecular; Promoter; Genetic; Proto-Oncogene Proteins B-raf

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF

Added On: 24/09/2015 13:08

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Genetics Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)