2ish: Difference between revisions

Line 1:

[[Image:2ish.gif|left|200px]]<br /><applet load="2ish" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

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

caption="2ish, resolution 2.00Å" />

'''Botulinum Neurotoxin A Light Chain WT Crystal Form C'''<br />

==Overview==

An efficient research strategy integrating empirically guided, structure-based modeling and chemoinformatics was used to discover potent, small molecule inhibitors of the botulinum neurotoxin serotype A light, chain. First, a modeled binding mode for inhibitor, 2-mercapto-3-phenylpropionyl-RATKML (K(i) = 330 nM) was generated, and, required the use of a molecular dynamic conformer of the enzyme displaying, the reorientation of surface loops bordering the substrate binding cleft., These flexible loops are conformationally variable in x-ray crystal, structures, and the model predicted that they were pivotal for providing, complementary binding surfaces and solvent shielding for the, pseudo-peptide. The docked conformation of, 2-mercapto-3-phenylpropionyl-RATKML was then used to refine our, pharmacophore for botulinum serotype A light chain inhibition. Data base, search queries derived from the pharmacophore were employed to mine small, molecule (non-peptidic) inhibitors from the National Cancer Institute's, Open Repository. Four of the inhibitors possess K(i) values ranging from, 3.0 to 10.0 microM. Of these, NSC 240898 is a promising lead for, therapeutic development, as it readily enters neurons, exhibits no, neuronal toxicity, and elicits dose-dependent protection of, synaptosomal-associated protein (of 25 kDa) in a primary culture of, embryonic chicken neurons. Isothermal titration calorimetry showed that, the interaction between NSC 240898 and the botulinum A light chain is, largely entropy-driven, and occurs with a 1:1 stoichiometry and a, dissociation constant of 4.6 microM.

An efficient research strategy integrating empirically guided, structure-based modeling and chemoinformatics was used to discover potent small molecule inhibitors of the botulinum neurotoxin serotype A light chain. First, a modeled binding mode for inhibitor 2-mercapto-3-phenylpropionyl-RATKML (K(i) = 330 nM) was generated, and required the use of a molecular dynamic conformer of the enzyme displaying the reorientation of surface loops bordering the substrate binding cleft. These flexible loops are conformationally variable in x-ray crystal structures, and the model predicted that they were pivotal for providing complementary binding surfaces and solvent shielding for the pseudo-peptide. The docked conformation of 2-mercapto-3-phenylpropionyl-RATKML was then used to refine our pharmacophore for botulinum serotype A light chain inhibition. Data base search queries derived from the pharmacophore were employed to mine small molecule (non-peptidic) inhibitors from the National Cancer Institute's Open Repository. Four of the inhibitors possess K(i) values ranging from 3.0 to 10.0 microM. Of these, NSC 240898 is a promising lead for therapeutic development, as it readily enters neurons, exhibits no neuronal toxicity, and elicits dose-dependent protection of synaptosomal-associated protein (of 25 kDa) in a primary culture of embryonic chicken neurons. Isothermal titration calorimetry showed that the interaction between NSC 240898 and the botulinum A light chain is largely entropy-driven, and occurs with a 1:1 stoichiometry and a dissociation constant of 4.6 microM.

==About this Structure==

2ISH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with ZN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2ISH OCA].

2ISH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ISH OCA].

==Reference==

Line 13:

[[Category: Clostridium botulinum]]

[[Category: Single protein]]

[[Category: Brunger, A.T.]]

[[Category: Brunger, A T.]]

[[Category: Stegmann, C.M.]]

[[Category: Stegmann, C M.]]

[[Category: ZN]]

[[Category: botulinum neurotoxin]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Tue Nov 20 15~~:29:~~36 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:55:25 2008''

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 1: / Line 1: @@
-[[Image:2ish.gif|left|200px]]<br /><applet load="2ish" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2ish.gif|left|200px]]<br /><applet load="2ish" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2ish, resolution 2.00&Aring;" />
 '''Botulinum Neurotoxin A Light Chain WT Crystal Form C'''<br />
 ==Overview==
-An efficient research strategy integrating empirically guided, structure-based modeling and chemoinformatics was used to discover potent, small molecule inhibitors of the botulinum neurotoxin serotype A light, chain. First, a modeled binding mode for inhibitor, 2-mercapto-3-phenylpropionyl-RATKML (K(i) = 330 nM) was generated, and, required the use of a molecular dynamic conformer of the enzyme displaying, the reorientation of surface loops bordering the substrate binding cleft., These flexible loops are conformationally variable in x-ray crystal, structures, and the model predicted that they were pivotal for providing, complementary binding surfaces and solvent shielding for the, pseudo-peptide. The docked conformation of, 2-mercapto-3-phenylpropionyl-RATKML was then used to refine our, pharmacophore for botulinum serotype A light chain inhibition. Data base, search queries derived from the pharmacophore were employed to mine small, molecule (non-peptidic) inhibitors from the National Cancer Institute's, Open Repository. Four of the inhibitors possess K(i) values ranging from, 3.0 to 10.0 microM. Of these, NSC 240898 is a promising lead for, therapeutic development, as it readily enters neurons, exhibits no, neuronal toxicity, and elicits dose-dependent protection of, synaptosomal-associated protein (of 25 kDa) in a primary culture of, embryonic chicken neurons. Isothermal titration calorimetry showed that, the interaction between NSC 240898 and the botulinum A light chain is, largely entropy-driven, and occurs with a 1:1 stoichiometry and a, dissociation constant of 4.6 microM.
+An efficient research strategy integrating empirically guided, structure-based modeling and chemoinformatics was used to discover potent small molecule inhibitors of the botulinum neurotoxin serotype A light chain. First, a modeled binding mode for inhibitor 2-mercapto-3-phenylpropionyl-RATKML (K(i) = 330 nM) was generated, and required the use of a molecular dynamic conformer of the enzyme displaying the reorientation of surface loops bordering the substrate binding cleft. These flexible loops are conformationally variable in x-ray crystal structures, and the model predicted that they were pivotal for providing complementary binding surfaces and solvent shielding for the pseudo-peptide. The docked conformation of 2-mercapto-3-phenylpropionyl-RATKML was then used to refine our pharmacophore for botulinum serotype A light chain inhibition. Data base search queries derived from the pharmacophore were employed to mine small molecule (non-peptidic) inhibitors from the National Cancer Institute's Open Repository. Four of the inhibitors possess K(i) values ranging from 3.0 to 10.0 microM. Of these, NSC 240898 is a promising lead for therapeutic development, as it readily enters neurons, exhibits no neuronal toxicity, and elicits dose-dependent protection of synaptosomal-associated protein (of 25 kDa) in a primary culture of embryonic chicken neurons. Isothermal titration calorimetry showed that the interaction between NSC 240898 and the botulinum A light chain is largely entropy-driven, and occurs with a 1:1 stoichiometry and a dissociation constant of 4.6 microM.
 ==About this Structure==
-ISH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with ZN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2ISH OCA].
+ISH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ISH OCA].
 ==Reference==
@@ Line 13: / Line 13: @@
 [[Category: Clostridium botulinum]]
 [[Category: Single protein]]
-[[Category: Brunger, A.T.]]
+[[Category: Brunger, A T.]]
-[[Category: Stegmann, C.M.]]
+[[Category: Stegmann, C M.]]
 [[Category: ZN]]
 [[Category: botulinum neurotoxin]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 15:29:36 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:55:25 2008''