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2no9

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[[Image:2no9.gif|left|200px]]<br /><applet load="2no9" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2no9.gif|left|200px]]
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caption="2no9, resolution 2.15&Aring;" />
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'''The structure of deoxycytidine kinase complexed with troxacitabine and ADP.'''<br />
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{{Structure
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|PDB= 2no9 |SIZE=350|CAPTION= <scene name='initialview01'>2no9</scene>, resolution 2.15&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=ADP:ADENOSINE-5'-DIPHOSPHATE'>ADP</scene> and <scene name='pdbligand=LTT:4-AMINO-1-[(2S,4S)-2-(HYDROXYMETHYL)-1,3-DIOXOLAN-4-YL]PYRIMIDIN-2(1H)-ONE'>LTT</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Deoxycytidine_kinase Deoxycytidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.74 2.7.1.74]
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|GENE= DCK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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}}
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'''The structure of deoxycytidine kinase complexed with troxacitabine and ADP.'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2NO9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=LTT:'>LTT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Deoxycytidine_kinase Deoxycytidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.74 2.7.1.74] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NO9 OCA].
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2NO9 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NO9 OCA].
==Reference==
==Reference==
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Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase., Sabini E, Hazra S, Konrad M, Burley SK, Lavie A, Nucleic Acids Res. 2007;35(1):186-92. Epub 2006 Dec 7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17158155 17158155]
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Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase., Sabini E, Hazra S, Konrad M, Burley SK, Lavie A, Nucleic Acids Res. 2007;35(1):186-92. Epub 2006 Dec 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17158155 17158155]
[[Category: Deoxycytidine kinase]]
[[Category: Deoxycytidine kinase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: troxacitabine]]
[[Category: troxacitabine]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:08:59 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:48:55 2008''

Revision as of 15:49, 20 March 2008

Image:2no9.gif


PDB ID 2no9

Drag the structure with the mouse to rotate
, resolution 2.15Å
Ligands: and
Gene: DCK (Homo sapiens)
Activity: Deoxycytidine kinase, with EC number 2.7.1.74
Coordinates: save as pdb, mmCIF, xml



The structure of deoxycytidine kinase complexed with troxacitabine and ADP.


Overview

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.

About this Structure

2NO9 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase., Sabini E, Hazra S, Konrad M, Burley SK, Lavie A, Nucleic Acids Res. 2007;35(1):186-92. Epub 2006 Dec 7. PMID:17158155

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