1rr8
From Proteopedia
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'''Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I''' | '''Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I''' | ||
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[[Category: Staker, B L.]] | [[Category: Staker, B L.]] | ||
[[Category: Stewart, L.]] | [[Category: Stewart, L.]] | ||
| - | [[Category: | + | [[Category: Camptothecin]] |
| - | [[Category: | + | [[Category: Human topoisomerase i]] |
| - | [[Category: | + | [[Category: Nucleic acid]] |
| - | [[Category: | + | [[Category: Protein-dna complex]] |
| - | [[Category: | + | [[Category: Topotecan]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:48:57 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 04:48, 3 May 2008
Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I
Contents |
Overview
Human topoisomerase I relaxes superhelical tension associated with DNA replication, transcription and recombination by reversibly nicking one strand of duplex DNA and forming a covalent 3'-phosphotyrosine linkage. This enzyme is the sole target of the camptothecin family of anticancer compounds, which acts by stabilizing the covalent protein-DNA complex and enhancing apoptosis through blocking the advancement of replication forks. Mutations that impart resistance to camptothecin have been identified in several regions of human topoisomerase I. We present the crystal structures of two camptothecin-resistant forms of human topoisomerase I (Phe361Ser at 2.6A resolution and Asn722Ser at 2.3A resolution) in ternary complexes with DNA and topotecan (Hycamtin), a camptothecin analogue currently in widespread clinical use. While the alteration of Asn722 to Ser leads to the elimination of a water-mediated contact between the enzyme and topotecan, we were surprised to find that a well-ordered water molecule replaces the hydrophobic phenylalanine side-chain in the Phe361Ser structure. We further consider camptothecin-resistant mutations at seven additional sites in human topoisomerase I and present structural evidence explaining their possible impact on drug binding. These results advance our understanding of the mechanism of cell poisoning by camptothecin and suggest specific modifications to the drug that may improve efficacy.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1RR8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Mechanisms of camptothecin resistance by human topoisomerase I mutations., Chrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, Redinbo MR, J Mol Biol. 2004 Jun 11;339(4):773-84. PMID:15165849 Page seeded by OCA on Sat May 3 07:48:57 2008
