1nh3
From Proteopedia
(New page: 200px<br /> <applet load="1nh3" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nh3, resolution 3.10Å" /> '''Human Topoisomerase...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1nh3.gif|left|200px]]<br /> | + | [[Image:1nh3.gif|left|200px]]<br /><applet load="1nh3" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1nh3" size=" | + | |
caption="1nh3, resolution 3.10Å" /> | caption="1nh3, resolution 3.10Å" /> | ||
'''Human Topoisomerase I Ara-C Complex'''<br /> | '''Human Topoisomerase I Ara-C Complex'''<br /> | ||
==Overview== | ==Overview== | ||
| - | 1-beta-d-Arabinofuranosylcytosine (Ara-C) is a potent antineoplastic drug | + | 1-beta-d-Arabinofuranosylcytosine (Ara-C) is a potent antineoplastic drug used in the treatment of acute leukemia. Previous biochemical studies indicated the incorporation of Ara-C into DNA reduced the catalytic activity of human topoisomerase I by decreasing the rate of single DNA strand religation by the enzyme by 2-3-fold. We present the 3.1 A crystal structure of human topoisomerase I in covalent complex with an oligonucleotide containing Ara-C at the +1 position of the non-scissile DNA strand. The structure reveals that a hydrogen bond formed between the 2'-hydroxyl of Ara-C and the O4' of the adjacent -1 base 5' to the damage site stabilizes a C3'-endo pucker in the Ara-C arabinose ring. The structural distortions at the site of damage are translated across the DNA double helix to the active site of human topoisomerase I. The free sulfhydryl at the 5'-end of the nicked DNA strand in this trapped covalent complex is shifted out of alignment with the 3'-phosphotyrosine linkage at the catalytic tyrosine 723 residue, producing a geometry not optimal for religation. The subtle structural changes caused by the presence of Ara-C in the DNA duplex may contribute to the cytotoxicity of this leukemia drug by prolonging the lifetime of the covalent human topoisomerase I-DNA complex. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1NH3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/DNA_topoisomerase DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.2 5.99.1.2] Full crystallographic information is available from [http:// | + | 1NH3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/DNA_topoisomerase DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.2 5.99.1.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NH3 OCA]. |
==Reference== | ==Reference== | ||
| Line 18: | Line 17: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Burgin, A | + | [[Category: Burgin, A B.]] |
| - | [[Category: Chrencik, J | + | [[Category: Chrencik, J E.]] |
[[Category: Pommier, Y.]] | [[Category: Pommier, Y.]] | ||
| - | [[Category: Redinbo, M | + | [[Category: Redinbo, M R.]] |
[[Category: Stewart, L.]] | [[Category: Stewart, L.]] | ||
[[Category: ara-c]] | [[Category: ara-c]] | ||
| Line 28: | Line 27: | ||
[[Category: protein-dna complex]] | [[Category: protein-dna complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:06:04 2008'' |
Revision as of 12:06, 21 February 2008
|
Human Topoisomerase I Ara-C Complex
Contents |
Overview
1-beta-d-Arabinofuranosylcytosine (Ara-C) is a potent antineoplastic drug used in the treatment of acute leukemia. Previous biochemical studies indicated the incorporation of Ara-C into DNA reduced the catalytic activity of human topoisomerase I by decreasing the rate of single DNA strand religation by the enzyme by 2-3-fold. We present the 3.1 A crystal structure of human topoisomerase I in covalent complex with an oligonucleotide containing Ara-C at the +1 position of the non-scissile DNA strand. The structure reveals that a hydrogen bond formed between the 2'-hydroxyl of Ara-C and the O4' of the adjacent -1 base 5' to the damage site stabilizes a C3'-endo pucker in the Ara-C arabinose ring. The structural distortions at the site of damage are translated across the DNA double helix to the active site of human topoisomerase I. The free sulfhydryl at the 5'-end of the nicked DNA strand in this trapped covalent complex is shifted out of alignment with the 3'-phosphotyrosine linkage at the catalytic tyrosine 723 residue, producing a geometry not optimal for religation. The subtle structural changes caused by the presence of Ara-C in the DNA duplex may contribute to the cytotoxicity of this leukemia drug by prolonging the lifetime of the covalent human topoisomerase I-DNA complex.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1NH3 is a Single protein structure of sequence from Homo sapiens. Active as DNA topoisomerase, with EC number 5.99.1.2 Full crystallographic information is available from OCA.
Reference
Structural impact of the leukemia drug 1-beta-D-arabinofuranosylcytosine (Ara-C) on the covalent human topoisomerase I-DNA complex., Chrencik JE, Burgin AB, Pommier Y, Stewart L, Redinbo MR, J Biol Chem. 2003 Apr 4;278(14):12461-6. Epub 2003 Jan 17. PMID:12533542
Page seeded by OCA on Thu Feb 21 14:06:04 2008
