دورية أكاديمية
أعرض في EDS

Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.

التفاصيل البيبلوغرافية
العنوان: Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
المؤلفون: Kelly L; Graduate Group in Bioinformatics, University of California at San Francisco, San Francisco, California, USA., Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, Sali A
المصدر: Protein science : a publication of the Protein Society [Protein Sci] 2010 Nov; Vol. 19 (11), pp. 2110-21.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Woodbury, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, N.Y. : Cambridge University Press, c1992-
مواضيع طبية MeSH: ATP-Binding Cassette Transporters/*chemistry, ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Adenine/analogs & derivatives ; Adenine/chemistry ; Adenine/metabolism ; Amino Acid Sequence ; Binding Sites ; Genetic Predisposition to Disease ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Sequence Annotation ; Molecular Sequence Data ; Multidrug Resistance-Associated Proteins/chemistry ; Multidrug Resistance-Associated Proteins/genetics ; Multidrug Resistance-Associated Proteins/metabolism ; Organophosphonates/chemistry ; Organophosphonates/metabolism ; Polymorphism, Single Nucleotide ; Protein Structure, Tertiary ; Reproducibility of Results ; Sequence Alignment ; Tenofovir
مستخلص: The human ATP-binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small α-helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease-associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.
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معلومات مُعتمدة: R01 GM54762 United States GM NIGMS NIH HHS; U01 GM61390 United States GM NIGMS NIH HHS; U54 GM074929 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (ABCC4 protein, human)
0 (ATP-Binding Cassette Transporters)
0 (Multidrug Resistance-Associated Proteins)
0 (Organophosphonates)
99YXE507IL (Tenofovir)
JAC85A2161 (Adenine)
تواريخ الأحداث: Date Created: 20100828 Date Completed: 20110224 Latest Revision: 20211020
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC3005782
DOI: 10.1002/pro.491
PMID: 20799350
قاعدة البيانات: MEDLINE
الوصف
تدمد:1469-896X
DOI:10.1002/pro.491