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| {{STRUCTURE_2no9| PDB=2no9 | SCENE= }} | | {{STRUCTURE_2no9| PDB=2no9 | SCENE= }} |
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| '''The structure of deoxycytidine kinase complexed with troxacitabine and ADP.'''
| | ===The structure of deoxycytidine kinase complexed with troxacitabine and ADP.=== |
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| ==Overview==
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| L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC)--an approved anti-human immunodeficiency virus (HIV) agent--and troxacitabine (TRO)--an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17158155}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17158155 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17158155}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: L-dc]] | | [[Category: L-dc]] |
| [[Category: Troxacitabine]] | | [[Category: Troxacitabine]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:41:57 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 05:12:22 2008'' |
