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PDBsum entry 4nsh
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References listed in PDB file
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Key reference
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Title
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Carboplatin binding to histidine.
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Authors
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S.W.Tanley,
K.Diederichs,
L.M.Kroon-Batenburg,
C.Levy,
A.M.Schreurs,
J.R.Helliwell.
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Ref.
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Acta Crystallogr F Struct Biol Commun, 2014,
70,
1135-1142.
[DOI no: ]
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PubMed id
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Abstract
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Carboplatin is a second-generation platinum anticancer agent used for the
treatment of a variety of cancers. Previous X-ray crystallographic studies of
carboplatin binding to histidine (in hen egg-white lysozyme; HEWL) showed the
partial conversion of carboplatin to cisplatin owing to the high NaCl
concentration used in the crystallization conditions. HEWL co-crystallizations
with carboplatin in NaBr conditions have now been carried out to confirm whether
carboplatin converts to the bromine form and whether this takes place in a
similar way to the partial conversion of carboplatin to cisplatin observed
previously in NaCl conditions. Here, it is reported that a partial chemical
transformation takes place but to a transplatin form. Thus, to attempt to
resolve purely carboplatin binding at histidine, this study utilized
co-crystallization of HEWL with carboplatin without NaCl to eliminate the
partial chemical conversion of carboplatin. Tetragonal HEWL crystals
co-crystallized with carboplatin were successfully obtained in four different
conditions, each at a different pH value. The structural results obtained show
carboplatin bound to either one or both of the N atoms of His15 of HEWL, and
this particular variation was dependent on the concentration of anions in the
crystallization mixture and the elapsed time, as well as the pH used. The
structural details of the bound carboplatin molecule also differed between them.
Overall, the most detailed crystal structure showed the majority of the
carboplatin atoms bound to the platinum centre; however, the four-carbon ring
structure of the cyclobutanedicarboxylate moiety (CBDC) remained elusive. The
potential impact of the results for the administration of carboplatin as an
anticancer agent are described.
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