1kjl: Difference between revisions
New page: left|200px<br /> <applet load="1kjl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kjl, resolution 1.4Å" /> '''High Resolution X-Ra... |
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[[Image:1kjl.gif|left|200px]]<br /> | [[Image:1kjl.gif|left|200px]]<br /><applet load="1kjl" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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'''High Resolution X-Ray Structure of Human Galectin-3 in complex with LacNAc'''<br /> | '''High Resolution X-Ray Structure of Human Galectin-3 in complex with LacNAc'''<br /> | ||
==Overview== | ==Overview== | ||
The high-resolution X-ray crystal structures of the carbohydrate | The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido ]-beta-D-galactopyranose)-beta-D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3'-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (K(d) > or = 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation-Pi interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions. | ||
==About this Structure== | ==About this Structure== | ||
1KJL 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 CL and BR as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1KJL 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=CL:'>CL</scene> and <scene name='pdbligand=BR:'>BR</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KJL OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Kahl-Knutsson, B.]] | [[Category: Kahl-Knutsson, B.]] | ||
[[Category: Leffler, H.]] | [[Category: Leffler, H.]] | ||
[[Category: Nilsson, U | [[Category: Nilsson, U J.]] | ||
[[Category: Rini, J | [[Category: Rini, J M.]] | ||
[[Category: Sorme, P.]] | [[Category: Sorme, P.]] | ||
[[Category: BR]] | [[Category: BR]] | ||
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[[Category: lacnac complex]] | [[Category: lacnac complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:34:54 2008'' | ||
Revision as of 14:34, 21 February 2008
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High Resolution X-Ray Structure of Human Galectin-3 in complex with LacNAc
OverviewOverview
The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido ]-beta-D-galactopyranose)-beta-D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3'-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (K(d) > or = 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation-Pi interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions.
About this StructureAbout this Structure
1KJL is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structural and thermodynamic studies on cation-Pi interactions in lectin-ligand complexes: high-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction., Sorme P, Arnoux P, Kahl-Knutsson B, Leffler H, Rini JM, Nilsson UJ, J Am Chem Soc. 2005 Feb 16;127(6):1737-43. PMID:15701008
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