Structural and Thermodynamic Studies on Cation--II Interactions in Lectin--Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine--Arene Interaction.
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| Title: | Structural and Thermodynamic Studies on Cation--II Interactions in Lectin--Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine--Arene Interaction. |
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| Authors: | Sörme, Pernilla1,2, Arnoux, Pascal3, Kahl-Knutsson, Barbro2, Leffler, Hakon2, Rini, James M.3, Niisson, Ulf J.1 ulf.nilsson@bioorganic.lth.se |
| Source: | Journal of the American Chemical Society. 2/16/2005, Vol. 127 Issue 6, p1737-1743. 7p. |
| Subjects: | Cations, Amino acids, Organic compounds, Volumetric analysis, Temperature measurements, Imino acids |
| Abstract: | 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]-β-d-galactopyranose)-β-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 (Kd ≥ 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-II 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. [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of the American Chemical Society is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 16207173 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Structural and Thermodynamic Studies on Cation--II Interactions in Lectin--Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine--Arene Interaction. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Sörme%2C+Pernilla%22">Sörme, Pernilla</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Arnoux%2C+Pascal%22">Arnoux, Pascal</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Kahl-Knutsson%2C+Barbro%22">Kahl-Knutsson, Barbro</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Leffler%2C+Hakon%22">Leffler, Hakon</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Rini%2C+James+M%2E%22">Rini, James M.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Niisson%2C+Ulf+J%2E%22">Niisson, Ulf J.</searchLink><relatesTo>1</relatesTo><i> ulf.nilsson@bioorganic.lth.se</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+the+American+Chemical+Society%22">Journal of the American Chemical Society</searchLink>. 2/16/2005, Vol. 127 Issue 6, p1737-1743. 7p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Cations%22">Cations</searchLink><br /><searchLink fieldCode="DE" term="%22Amino+acids%22">Amino acids</searchLink><br /><searchLink fieldCode="DE" term="%22Organic+compounds%22">Organic compounds</searchLink><br /><searchLink fieldCode="DE" term="%22Volumetric+analysis%22">Volumetric analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Temperature+measurements%22">Temperature measurements</searchLink><br /><searchLink fieldCode="DE" term="%22Imino+acids%22">Imino acids</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: 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]-β-d-galactopyranose)-β-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 (Kd ≥ 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-II 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. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of the American Chemical Society is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1021/ja043475p Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 7 StartPage: 1737 Subjects: – SubjectFull: Cations Type: general – SubjectFull: Amino acids Type: general – SubjectFull: Organic compounds Type: general – SubjectFull: Volumetric analysis Type: general – SubjectFull: Temperature measurements Type: general – SubjectFull: Imino acids Type: general Titles: – TitleFull: Structural and Thermodynamic Studies on Cation--II Interactions in Lectin--Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine--Arene Interaction. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Sörme, Pernilla – PersonEntity: Name: NameFull: Arnoux, Pascal – PersonEntity: Name: NameFull: Kahl-Knutsson, Barbro – PersonEntity: Name: NameFull: Leffler, Hakon – PersonEntity: Name: NameFull: Rini, James M. – PersonEntity: Name: NameFull: Niisson, Ulf J. IsPartOfRelationships: – BibEntity: Dates: – D: 16 M: 02 Text: 2/16/2005 Type: published Y: 2005 Identifiers: – Type: issn-print Value: 00027863 Numbering: – Type: volume Value: 127 – Type: issue Value: 6 Titles: – TitleFull: Journal of the American Chemical Society Type: main |
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