| Insight into TPMT(∗)23 mutation mis-folding using molecular dynamics simulation and protein structure analysis. | |
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MedLine Citation:
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PMID: 23025308 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Thiopurine S-methyltransferase (TPMT) is an important enzyme that metabolizes thiopurine drugs. This enzyme exhibits a large number of interindividual polymorphism. TPMT(∗)23 polymorphism has been reported in a few cases in the world in co-dominance with TPMT(∗)3A. The phenotype has been reported to affect enzyme activity in vivo and in vitro. Its underlying structural basis is not clarified yet. In our study, the wild type (WT) protein structure was analyzed and the amino acids bordering water channels in thiopurine sites were identified. Molecular dynamics of both the WT and TPMT(∗)23 mutation was carried out. In addition, the effects of this mutation, especially on the thiopurine site which is closed with a pincer like mechanism, were investigated. We focused on explaining how a locally occurred A167G substitution propagated through hydrogen bonds alteration to induce structural modification which affects both thiopurine and S-adenosylmethionine receptors. Finally, a genetic prediction of mutation functional consequences has been conducted confirming altered activity. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:20. |
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Authors:
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Sofiene Larif; Chaker Ben Salem; Zohra Soua; Houssem Hmouda; Kamel Bouraoui |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-2 |
Journal Detail:
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Title: Journal of biomolecular structure & dynamics Volume: - ISSN: 1538-0254 ISO Abbreviation: J. Biomol. Struct. Dyn. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-2 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8404176 Medline TA: J Biomol Struct Dyn Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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a Faculty of Medicine of Sousse, Metabolic Biophysics and Applied Pharmacology Laboratory, Department of Biophysics , Avenue Mohamed Karoui , Sousse , 4002 , Tunisia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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