Source:http://linkedlifedata.com/resource/pubmed/id/15649894
Switch to
Predicate | Object |
---|---|
rdf:type | |
lifeskim:mentions | |
pubmed:issue |
12
|
pubmed:dateCreated |
2005-3-21
|
pubmed:abstractText |
The equilibrative nucleoside transporters, hENT1 and CeENT1 from humans and Caenorhabditis elegans, respectively, are inhibited by nanomolar concentrations of dipyridamole and share a common 11-transmembrane helix (TM) topology. Random mutagenesis and screening by functional complementation in yeast for clones with reduced sensitivities to dipyridamole yielded mutations at Ile429 in TM 11 of CeENT1 and Met33 in TM 1 of hENT1. Mutational analysis of the corresponding residues of both proteins suggested important roles for these residues in competitive inhibition of hENT1 and CeENT1 by dipyridamole. To verify the roles of these residues in dipyridamole interactions, hENT2, which naturally exhibits low dipyridamole sensitivity, was mutated to contain side chains favorable for high affinity dipyridamole binding (i.e. a Met at the TM 1 and/or an Ile at the TM 11 positions). The single mutants exhibited increased hENT2 sensitivity to inhibition by dipyridamole, and the double mutant was the most sensitive, with an IC50 value that was only 2% of that of wild type. Functional analysis of the TM 1 and 11 mutants of hENT1 and CeENT1 revealed that Ala and Thr in the TM 1 and 11 positions, respectively, impaired uridine and adenosine transport and that Leu442 of hENT1 was involved in permeant selectivity. Mechanistic and structural models of dipyridamole interactions with the TM 1 and 11 residues are proposed. This study demonstrated that the corresponding residues in TMs 1 and 11 of hENT1, hENT2, and CeENT1 are important for dipyridamole interactions and nucleoside transport.
|
pubmed:language |
eng
|
pubmed:journal | |
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine,
http://linkedlifedata.com/resource/pubmed/chemical/Caenorhabditis elegans Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Dipyridamole,
http://linkedlifedata.com/resource/pubmed/chemical/Equilibrative Nucleoside...,
http://linkedlifedata.com/resource/pubmed/chemical/Equilibrative-Nucleoside...,
http://linkedlifedata.com/resource/pubmed/chemical/SLC29A1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SLC29A2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Uridine
|
pubmed:status |
MEDLINE
|
pubmed:month |
Mar
|
pubmed:issn |
0021-9258
|
pubmed:author | |
pubmed:issnType |
Print
|
pubmed:day |
25
|
pubmed:volume |
280
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
11025-34
|
pubmed:dateRevised |
2006-11-15
|
pubmed:meshHeading |
pubmed-meshheading:15649894-Adenosine,
pubmed-meshheading:15649894-Amino Acid Sequence,
pubmed-meshheading:15649894-Binding Sites,
pubmed-meshheading:15649894-Caenorhabditis elegans Proteins,
pubmed-meshheading:15649894-Dipyridamole,
pubmed-meshheading:15649894-Dose-Response Relationship, Drug,
pubmed-meshheading:15649894-Equilibrative Nucleoside Transporter 1,
pubmed-meshheading:15649894-Equilibrative-Nucleoside Transporter 2,
pubmed-meshheading:15649894-Humans,
pubmed-meshheading:15649894-Models, Molecular,
pubmed-meshheading:15649894-Molecular Sequence Data,
pubmed-meshheading:15649894-Mutation,
pubmed-meshheading:15649894-Structure-Activity Relationship,
pubmed-meshheading:15649894-Uridine
|
pubmed:year |
2005
|
pubmed:articleTitle |
Identification and mutational analysis of amino acid residues involved in dipyridamole interactions with human and Caenorhabditis elegans equilibrative nucleoside transporters.
|
pubmed:affiliation |
Membrane Protein Research Group, Department of Oncology, University of Alberta, and the Cross Cancer Institute, Edmonton, Alberta, Canada.
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|