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  • Open Daily: 10am - 10pm
    Alley-side Pickup: 10am - 7pm

    3038 Hennepin Ave Minneapolis, MN
    612-822-4611

Open Daily: 10am - 10pm | Alley-side Pickup: 10am - 7pm
3038 Hennepin Ave Minneapolis, MN
612-822-4611
Chemical Approaches Towards Capturing and Imaging a Topoisomerase-DNA Complex.

Chemical Approaches Towards Capturing and Imaging a Topoisomerase-DNA Complex.

Dong, Ken Chu

Paperback

Chemistry

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ISBN10: 1243635185
ISBN13: 9781243635181
Publisher: Proquest Umi Dissertation Pub
Pages: 168
Weight: 0.69
Height: 0.36 Width: 7.44 Depth: 9.69
Language: English
Type IIA topoisomerases are essential enzymes necessary for resolving topological problems that arise during the transcription and replication of DNA. Despite several decades study, a molecular understanding of how this enzyme interacts with DNA, its principle substrate, has been lacking. This gap has left several outstanding mechanistic questions, including how the enzyme recognizes its DNA substrate, unanswered. The main challenge of imaging this complex is that the enzyme lacks sequence-specificity, making crystallography and other imaging techniques difficult. The central hypothesis of this project is that covalent and non-covalent chemical approaches can be used to help overcome this problem. A number of these methods were used to try and capture this complex for crystallography including engineering a sequence-specific enzyme using polyamides, using a transition-state analogue to capture a covalent complex, and using disulfide chemistry to covalently attach the DNA to the protein. Only the use of nicked-DNA was successful in the crystallization of a topoisomerase-DNA complex. This structure reveals the molecular mechanism of Gate-DNA recognition and bending, explains how DNA binding and cleavage are uncoupled, and provides an intermediate step key in the two-gate mechanism. The structure also reinforces structural similarities between type IA and type IIA topoisomerases, and rationalizes decades of drug-resistance biochemistry.

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