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Dissecting the micr...
Dissecting the microscopic steps of the cyclophilin a enzymatic cycle on the biological substrate HIV-capsid by NMR
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- Bosco, Daryl A (författare)
- Department of Biochemistry and Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA
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- Eisenmesser, Elan Zohar (författare)
- Department of Biochemistry and Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA
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- Clarkson, Michael W (författare)
- Department of Biochemistry and Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA
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- Wolf-Watz, Magnus (författare)
- Umeå universitet,Kemiska institutionen
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- Labeikovsky, Wladimir (författare)
- Department of Biochemistry and Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA
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- Millet, Oscar (författare)
- Protein Engineering Network Center of Excellence and Departments of Medical Genetics, Biochemistry, Canada
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- Kern, Dorothee (författare)
- Department of Biochemistry and Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA
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(creator_code:org_t)
- Elsevier, 2010
- 2010
- Engelska.
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Ingår i: Journal of Molecular Biology. - : Elsevier. - 0022-2836 .- 1089-8638. ; 403:5, s. 723-38
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Peptidyl-prolyl isomerases (PPIases) are emerging as key regulators of many diverse biological processes. Elucidating the role of PPIase activity in vivo has been challenging because mutagenesis of active site residues not only reduces the catalytic activity of these enzymes, but also dramatically affects substrate binding. Employing the cyclophilin A (CypA) PPIase together with its biologically relevant and natively folded substrate, the N-terminal domain of the HIV-1 capsid (CA(N)) protein, we demonstrate here how to dissect residue specific contributions to PPIase catalysis versus substrate binding utilizing NMR spectroscopy. Surprisingly, a number of CypA active-site mutants previously assumed to be strongly diminished in activity toward biological substrates based on a peptide assay only, catalyze the HIV capsid with wild-type activity, but with a change in the rate-limiting step of the enzymatic cycle. The results illustrate that a quantitative analysis of catalysis using the biological substrates is critical when interpreting the effects of PPIase mutations in biological assays.
Nyckelord
- cyclophilin A
- prolyl isomerase
- HIV-1 replication
- NMR
- backbone dynamics
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- art (ämneskategori)
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