Exploring the recognition of quadruplex DNA by an engineered Cys2-His2 zinc finger protein

Ladame, S., Schouten, J.A., Roldan, J., Redman, J.E., Neidle, S. and Balasubramanian, S. (2006) Exploring the recognition of quadruplex DNA by an engineered Cys2-His2 zinc finger protein. Biochemistry, 45 (5). pp. 1393-1399. 10.1021/bi050229x.

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DOI: 10.1021/bi050229x

Abstract

Exploring the Recognition of Quadruplex DNA by an Engineered Cys2-His2 Zinc Finger Protein Sylvain Ladame, James A. Schouten, Jose Roldan, James E. Redman, Stephen Neidle, and Shankar Balasubramanian* University Chemical Laboratories, University of Cambridge, Lensfield Road, Cambridge CB21EW, U.K., and Cancer Research U.K. Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, U.K. Received February 8, 2005 Revised Manuscript Received November 22, 2005 Abstract: We have recently described an engineered zinc finger protein (Gq1) that binds with high specificity to the intramolecular G-quadruplex formed by the human telomeric sequence 5'-(GGTTAG)5-3', and that inhibits the activity of the enzyme telomerase in vitro. Here we report site-directed mutagenesis, biophysical, and molecular modeling studies that provide new insights into quadruplex recognition by the zinc finger scaffold. We show that any one finger of Gq1 can be replaced with the corresponding finger of Zif268, without significant loss of quadruplex affinity or quadruplex versus duplex discrimination. Replacement of two fingers, with one being finger 2, of Gq1 by Zif268 results in significant impairment of quadruplex recognition and loss of discrimination. Molecular modeling suggests that the zinc fingers of Gq1 can bind to the human parallel-stranded quadruplex structure in a stable arrangement, whereas Zif268-quadruplex models show significantly weaker binding energy. Modeling also suggests that an important role of the key protein finger residues in the Gq1-quadruplex complex is to maintain Gq1 in an optimum conformation for quadruplex recognition.

Item Type:Article
Additional Information:Full text available in print and electronically at the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group
ID Code:775
Journal or Publication Title:Biochemistry
Deposited By:Library Staff
Deposited On:21 Jun 2007
Last Modified:04 Nov 2011 14:42

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