2no9: Difference between revisions

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[[Image:2no9.gif|left|200px]]<br />

[[Image:2no9.gif|left|200px]]<br /><applet load="2no9" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="2no9" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="2no9, resolution 2.15Å" />

'''The structure of deoxycytidine kinase complexed with troxacitabine and ADP.'''<br />

==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.

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 [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ADP and LTT 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://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2NO9 OCA].

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].

==Reference==

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[[Category: troxacitabine]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 23~~:00:~~40 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:08:59 2008''

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@@ Line 1: / Line 1: @@
-[[Image:2no9.gif|left|200px]]<br />
+[[Image:2no9.gif|left|200px]]<br /><applet load="2no9" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2no9" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2no9, resolution 2.15&Aring;" />
 '''The structure of deoxycytidine kinase complexed with troxacitabine and ADP.'''<br />
 ==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.
+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==
-NO9 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 ADP and LTT 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2NO9 OCA].
+NO9 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].
 ==Reference==
@@ Line 26: / Line 25: @@
 [[Category: troxacitabine]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:00:40 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:08:59 2008''