1ckt: Difference between revisions
New page: left|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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[[Image:1ckt.gif|left|200px]]<br /><applet load="1ckt" size=" | [[Image:1ckt.gif|left|200px]]<br /><applet load="1ckt" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1ckt, resolution 2.5Å" /> | caption="1ckt, resolution 2.5Å" /> | ||
'''CRYSTAL STRUCTURE OF HMG1 DOMAIN A BOUND TO A CISPLATIN-MODIFIED DNA DUPLEX'''<br /> | '''CRYSTAL STRUCTURE OF HMG1 DOMAIN A BOUND TO A CISPLATIN-MODIFIED DNA DUPLEX'''<br /> | ||
==Overview== | ==Overview== | ||
The anticancer activity of cis-diamminedichloroplatinum(II) (cisplatin) | 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== | ==About this Structure== | ||
1CKT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with CPT as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 1CKT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=CPT:'>CPT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CKT OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Lippard, S | [[Category: Lippard, S J.]] | ||
[[Category: Ohndorf, U | [[Category: Ohndorf, U M.]] | ||
[[Category: Pabo, C | [[Category: Pabo, C O.]] | ||
[[Category: Rould, M | [[Category: Rould, M A.]] | ||
[[Category: CPT]] | [[Category: CPT]] | ||
[[Category: bent dna]] | [[Category: bent dna]] | ||
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[[Category: protein-drug-dna complex]] | [[Category: protein-drug-dna complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:07:05 2008'' | ||
Revision as of 13:07, 21 February 2008
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CRYSTAL STRUCTURE OF HMG1 DOMAIN A BOUND TO A CISPLATIN-MODIFIED DNA DUPLEX
OverviewOverview
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 StructureAbout this Structure
1CKT is a Single protein structure of sequence from Rattus norvegicus with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
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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