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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2010-2-17
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pubmed:databankReference |
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pubmed:abstractText |
Structure-based drug design is underway to inhibit the S100B-p53 interaction as a strategy for treating malignant melanoma. X-ray crystallography was used here to characterize an interaction between Ca(2)(+)-S100B and TRTK-12, a target that binds to the p53-binding site on S100B. The structures of Ca(2+)-S100B (1.5-A resolution) and S100B-Ca(2)(+)-TRTK-12 (2.0-A resolution) determined here indicate that the S100B-Ca(2+)-TRTK-12 complex is dominated by an interaction between Trp7 of TRTK-12 and a hydrophobic binding pocket exposed on Ca(2+)-S100B involving residues in helices 2 and 3 and loop 2. As with an S100B-Ca(2)(+)-p53 peptide complex, TRTK-12 binding to Ca(2+)-S100B was found to increase the protein's Ca(2)(+)-binding affinity. One explanation for this effect was that peptide binding introduced a structural change that increased the number of Ca(2+) ligands and/or improved the Ca(2+) coordination geometry of S100B. This possibility was ruled out when the structures of S100B-Ca(2+)-TRTK-12 and S100B-Ca(2+) were compared and calcium ion coordination by the protein was found to be nearly identical in both EF-hand calcium-binding domains (RMSD=0.19). On the other hand, B-factors for residues in EF2 of Ca(2+)-S100B were found to be significantly lowered with TRTK-12 bound. This result is consistent with NMR (15)N relaxation studies that showed that TRTK-12 binding eliminated dynamic properties observed in Ca(2+)-S100B. Such a loss of protein motion may also provide an explanation for how calcium-ion-binding affinity is increased upon binding a target. Lastly, it follows that any small-molecule inhibitor bound to Ca(2+)-S100B would also have to cause an increase in calcium-ion-binding affinity to be effective therapeutically inside a cell, so these data need to be considered in future drug design studies involving S100B.
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pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/CA107331,
http://linkedlifedata.com/resource/pubmed/grant/GM58888,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA107331-01A3,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA107331-02,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA107331-03,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA107331-04,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA107331-04S1,
http://linkedlifedata.com/resource/pubmed/grant/R01 GM058888-08,
http://linkedlifedata.com/resource/pubmed/grant/R01 GM058888-09,
http://linkedlifedata.com/resource/pubmed/grant/R01 GM058888-10,
http://linkedlifedata.com/resource/pubmed/grant/R01 GM058888-11,
http://linkedlifedata.com/resource/pubmed/grant/R01 GM058888-11S1,
http://linkedlifedata.com/resource/pubmed/grant/S10 RR015741-01,
http://linkedlifedata.com/resource/pubmed/grant/S10 RR016812-01,
http://linkedlifedata.com/resource/pubmed/grant/S10 RR023447-01
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-10187847,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-10191501,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-10211826,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-10493575,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-10592235,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-10876243,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11390274,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11454863,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11567159,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11833360,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11888280,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11937060,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-11969402,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-12470955,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-12480931,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-12645002,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-14087380,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-14661952,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15178678,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15299926,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15318002,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15325294,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15388930,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15572765,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-15882069,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-16683912,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-1676297,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-17010455,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-1702994,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-18949447,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-19452629,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-2673026,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-3513826,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-3567171,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-3722150,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-4376581,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-4953930,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-5482765,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-5933875,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-7410354,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-7540176,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-7627436,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-7830587,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-8520220,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-8589606,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-8794737,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-8805590,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9232658,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9245399,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9485322,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9485423,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9519411,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9519413,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20053360-9818269
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1089-8638
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pubmed:author |
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