1ckt
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(New page: 200px<br /><applet load="1ckt" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ckt, resolution 2.5Å" /> '''CRYSTAL STRUCTURE OF ...)
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Revision as of 10:25, 20 November 2007
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CRYSTAL STRUCTURE OF HMG1 DOMAIN A BOUND TO A CISPLATIN-MODIFIED DNA DUPLEX
Overview
The anticancer activity of cis-diamminedichloroplatinum(II) (cisplatin), arises from its ability to damage DNA, with the major adducts formed being, intrastrand d(GpG) and d(ApG) crosslinks. These crosslinks bend and unwind, the duplex, and the altered structure attracts high-mobility-group domain, (HMG) and other proteins. This binding of HMG-domain proteins to, cisplatin-modified DNA has been postulated to mediate the antitumour, properties of the drug. Many HMG-domain proteins recognize altered DNA, structures such as four-way junctions and cisplatin-modified DNA, but, until now the molecular basis for this recognition was unknown. Here we, describe mutagenesis, hydroxyl-radical footprinting and X-ray studies that, elucidate the structure of a 1:1 cisplatin-modified DNA/HMG-domain, complex. Domain A of the structure-specific HMG-domain protein HMG1 binds, to the widened minor groove of a 16-base-pair DNA duplex containing a, site-specific cis-[Pt(NH3)2[d(GpG)-N7(1),-N7(2)]] adduct. The DNA is, strongly kinked at a hydrophobic notch created at the platinum-DNA, crosslink and protein binding extends exclusively to the 3' side of the, platinated strand. A phenylalanine residue at position 37 intercalates, into a hydrophobic notch created at the platinum crosslinked d(GpG) site, and binding of the domain is dramatically reduced in a mutant in which, alanine is substituted for phenylalanine at this position.
About this Structure
1CKT is a Single protein structure of sequence from Rattus norvegicus with CPT as ligand. Full crystallographic information is available from OCA.
Reference
Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins., Ohndorf UM, Rould MA, He Q, Pabo CO, Lippard SJ, Nature. 1999 Jun 17;399(6737):708-12. PMID:10385126
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