1pzi
From Proteopedia
(New page: 200px<br /><applet load="1pzi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pzi, resolution 1.99Å" /> '''Heat-Labile Enteroto...) |
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| - | [[Image:1pzi.gif|left|200px]]<br /><applet load="1pzi" size=" | + | [[Image:1pzi.gif|left|200px]]<br /><applet load="1pzi" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pzi, resolution 1.99Å" /> | caption="1pzi, resolution 1.99Å" /> | ||
'''Heat-Labile Enterotoxin B-Pentamer Complexed With Nitrophenyl Galactoside 2a'''<br /> | '''Heat-Labile Enterotoxin B-Pentamer Complexed With Nitrophenyl Galactoside 2a'''<br /> | ||
==Overview== | ==Overview== | ||
| - | With the aim of developing high-affinity mono and multivalent antagonists | + | With the aim of developing high-affinity mono and multivalent antagonists of cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) we are using the galactose portion of the natural receptor ganglioside GM1 as an anchoring fragment in structure-based inhibitor design efforts. In order to establish a better structure-activity relationship for guiding these studies, we designed and prepared a small focused library of twenty 3,5-substituted phenylgalactosides based on two previous leads. The compounds were tested for their ability to block CTB(5) binding to immobilized ganglioside receptor and compared to the two previous leads. The crystal structures of the most promising compounds bound to either CTB(5) or LTB(5) were then determined in order to understand the basis for affinity differences. The most potent new compound yielded a six-fold improvement over our benchmark lead m-nitrophenyl-alpha-d-galactopyranoside (MNPG), and a two-fold improvement in IC(50) over a newer MNPG derivative. These results support the notion that the m-nitrophenyl moiety of MNPG and its derivatives is an important element to retain in future optimization efforts. Additionally, a consensus binding-pocket for the alkylmorpholine or piperazine moiety present in all of the designed antagonists was established as an important area of the GM1 binding site to target in future work. |
==About this Structure== | ==About this Structure== | ||
| - | 1PZI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with 1DM as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1PZI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=1DM:'>1DM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PZI OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Fan, E.]] | [[Category: Fan, E.]] | ||
| - | [[Category: Hol, W | + | [[Category: Hol, W G.J.]] |
[[Category: Korotkov, K.]] | [[Category: Korotkov, K.]] | ||
| - | [[Category: Mitchell, D | + | [[Category: Mitchell, D D.]] |
| - | [[Category: Pickens, J | + | [[Category: Pickens, J C.]] |
[[Category: 1DM]] | [[Category: 1DM]] | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
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[[Category: toxin]] | [[Category: toxin]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:34:17 2008'' |
Revision as of 12:34, 21 February 2008
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Heat-Labile Enterotoxin B-Pentamer Complexed With Nitrophenyl Galactoside 2a
Overview
With the aim of developing high-affinity mono and multivalent antagonists of cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) we are using the galactose portion of the natural receptor ganglioside GM1 as an anchoring fragment in structure-based inhibitor design efforts. In order to establish a better structure-activity relationship for guiding these studies, we designed and prepared a small focused library of twenty 3,5-substituted phenylgalactosides based on two previous leads. The compounds were tested for their ability to block CTB(5) binding to immobilized ganglioside receptor and compared to the two previous leads. The crystal structures of the most promising compounds bound to either CTB(5) or LTB(5) were then determined in order to understand the basis for affinity differences. The most potent new compound yielded a six-fold improvement over our benchmark lead m-nitrophenyl-alpha-d-galactopyranoside (MNPG), and a two-fold improvement in IC(50) over a newer MNPG derivative. These results support the notion that the m-nitrophenyl moiety of MNPG and its derivatives is an important element to retain in future optimization efforts. Additionally, a consensus binding-pocket for the alkylmorpholine or piperazine moiety present in all of the designed antagonists was established as an important area of the GM1 binding site to target in future work.
About this Structure
1PZI is a Single protein structure of sequence from Escherichia coli with as ligand. Full crystallographic information is available from OCA.
Reference
3,5-Substituted phenyl galactosides as leads in designing effective cholera toxin antagonists; synthesis and crystallographic studies., Mitchell DD, Pickens JC, Korotkov K, Fan E, Hol WG, Bioorg Med Chem. 2004 Mar 1;12(5):907-20. PMID:14980603
Page seeded by OCA on Thu Feb 21 14:34:17 2008
Categories: Escherichia coli | Single protein | Fan, E. | Hol, W G.J. | Korotkov, K. | Mitchell, D D. | Pickens, J C. | 1DM | Inhibitor | Monovalent | Pentamer | Toxin
