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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
4
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pubmed:dateCreated |
1996-5-30
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pubmed:abstractText |
Cys118, in the third membrane-spanning segment of the dopamine D2 receptor, is exposed in the binding-site crevice. Cys118 reacts with the highly polar, sulfhydryl-specific reagents methanethiosulfonate ethylammonium (MTSEA) and methanethiosulfonate ethyltrimethylammonium (MTSET), and this reaction is retarded by the presence of antagonists and agonists. The reaction of MTSEA covalently attaches-SCH2CH2NH3+ to the cysteine sulfhydryl, producing a lysine-like side chain. The reaction of MTSEA with Cys118 decreased the affinity of substituted-benzamide antagonists, such as YM-09151-2, by 50-2800-fold, whereas the affinities of other antagonists, such as N-methyl-spiperone, were decreased < / = 6-fold. Agonist affinities were decreased 3-12,000-fold. Mutation of Cys118 to Lys had effects similar to that of the reaction of Cys118 with MTSEA. In contrast, mutation to the uncharged Met, the side-chain volume of which is similar to that of Lys, had much lesser effects on binding. All of the agonists and antagonists contain a positively charged nitrogen that is thought to interact with the side chain of Asp114, located one alpha-helical turn above Cys118. If this nitrogen is close to Asp114, then in the substituted-benzamides, the group on the nitrogen or the pyrrolidine ring itself could extend toward Cys118. Modification of Cys118 would then interfere with binding. The reaction of MTSET with Cys118 covalently attaches-SCH2CH2N(CH3)3+, which is bulkier and approximately 2 angstroms longer than the -SCH2CH2NH3+ added by MTSEA. In contrast to MTSEA, MTSET had equally large effects on the binding of YM-09151-2 and N-methyl-spiperone. Therefore, the effect on binding depends on both the size and the charge of the side chain substituted for that of Cys118.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3-N-methylspiperone,
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Dopamine D2,
http://linkedlifedata.com/resource/pubmed/chemical/Spiperone,
http://linkedlifedata.com/resource/pubmed/chemical/nemonapride
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0026-895X
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
692-8
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:8609898-Benzamides,
pubmed-meshheading:8609898-Binding Sites,
pubmed-meshheading:8609898-Cell Line,
pubmed-meshheading:8609898-Cysteine,
pubmed-meshheading:8609898-Humans,
pubmed-meshheading:8609898-Mutagenesis, Site-Directed,
pubmed-meshheading:8609898-Receptors, Dopamine D2,
pubmed-meshheading:8609898-Spiperone,
pubmed-meshheading:8609898-Structure-Activity Relationship
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pubmed:year |
1996
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pubmed:articleTitle |
Differentiating dopamine D2 ligands by their sensitivities to modification of the cysteine exposed in the binding-site crevice.
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pubmed:affiliation |
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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