Crystallographic studies of protein-ligand interactions in the galectin family
(2025) KFKM05 20251Biophysical Chemistry
- Abstract
- The aim of this thesis was to study protein-ligand interactions in the binding pocket of galectin-3C and galectin-8N through X-ray crystallography. Ligands in different stages of their development state were crystallized in complex with their respective target protein. In total, two protein-ligand complexes were structurally solved for galectin-3C, and one partially for galectin-8N. The structures along with their final models are presented in this report. The galectin-3C structures either confirmed interactions of previously unsolved functional groups, and/or provided insights into further optimization of the ligands in terms of structure-activity relationship and galectin inhibitor design.
- Popular Abstract
- Investigating protein-drug interactions to improve efficiency in drug design
Galectins are a small family of proteins - but a big player in biological processes and consequent diseases. By studying the structure of drugs and proteins bound together, further improvements can be made to construct better drugs.
Galectins have shown a broad involvement in several diseases - all stages of tumour development, neurodegenerative diseases, inflammation and scar tissue formation. This puts a great need on developing new drugs to combat said diseases. Today, efforts are made to target the carbohydrate recognition domain of galectins, CRD - the part through which it exerts its function. By mimicking the sugar rings galectins traditionally... (More) - Investigating protein-drug interactions to improve efficiency in drug design
Galectins are a small family of proteins - but a big player in biological processes and consequent diseases. By studying the structure of drugs and proteins bound together, further improvements can be made to construct better drugs.
Galectins have shown a broad involvement in several diseases - all stages of tumour development, neurodegenerative diseases, inflammation and scar tissue formation. This puts a great need on developing new drugs to combat said diseases. Today, efforts are made to target the carbohydrate recognition domain of galectins, CRD - the part through which it exerts its function. By mimicking the sugar rings galectins traditionally bind, drugs can trick the protein to bind them instead of exerting its function. To make the drugs better, different chemical groups are added to the drug to improve binding strength, solubility and selectivity over its natural target.
These characteristics are an important part to know when designing drugs. One way of knowing how interactions take place is to study the structure of the drug and protein in combination through X-ray crystallography. Proteins and ligands are mixed with chemicals to form crystals, which are then exposed to X-rays. The way the X-rays diffract correspond to the positions of all molecules in the crystal. By conducting computational transformations and building models, a 3-dimensional structure that visualizes the drug interaction can be obtained.
In this project, 8 drugs targeting variants of either galectin 3 and galectin 8 were investigated. The drugs were in different stages of development, each with individual differences to study.
Regardless of repeated efforts, only three structures could be decoded. Contamination of sugar residues remaining from the protein purification outcompeted the drugs targeting galectin 3. Despite working for galectin 8 and the drugs having a theoretically much higher ability to bind the protein, lactose residues were bound. This problem is currently being solved through altering the protein production. For galectin 8, one drug did not form crystals, whereas another formed atypically shaped crystals that could not be exposed to x-rays.
Of the successful drugs, high-quality data was obtained - structures could be studied down to an atomic level and the quality of obtained data was very good. For galectin 3, the drug GB-1265 successfully showed presence and selectivity for a newly introduced group. The precursor drug FS-E332 gained insight into the orientation of a side chain within the protein, as well as important insights on how to improve its structure and binding. For galectin 8, the drug AMM-153 reacted with water in the solution leading to half of it missing.
Despite the hardships endured, results from the successful drugs provided valuable insights and a direction for the future to develop better drugs with the help of X-ray crystallography. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9200554
- author
- Åberg, Ludvig LU
- supervisor
-
- Derek Logan LU
- Erica Ahl LU
- organization
- course
- KFKM05 20251
- year
- 2025
- type
- H3 - Professional qualifications (4 Years - )
- subject
- keywords
- galectins, X-ray crystallography, structural biology, drug design, inhibitors, biophysical chemistry
- language
- English
- id
- 9200554
- date added to LUP
- 2025-06-17 08:40:13
- date last changed
- 2025-06-17 08:40:13
@misc{9200554,
abstract = {{The aim of this thesis was to study protein-ligand interactions in the binding pocket of galectin-3C and galectin-8N through X-ray crystallography. Ligands in different stages of their development state were crystallized in complex with their respective target protein. In total, two protein-ligand complexes were structurally solved for galectin-3C, and one partially for galectin-8N. The structures along with their final models are presented in this report. The galectin-3C structures either confirmed interactions of previously unsolved functional groups, and/or provided insights into further optimization of the ligands in terms of structure-activity relationship and galectin inhibitor design.}},
author = {{Åberg, Ludvig}},
language = {{eng}},
note = {{Student Paper}},
title = {{Crystallographic studies of protein-ligand interactions in the galectin family}},
year = {{2025}},
}