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Structure and energetics of molecular recognition in galectin-3-ligand interactions

Kumar, Rohit LU (2019)
Abstract
Molecular recognition is the key aspect of any cellular and biological function. Two or more molecules interacting with each other cause the effects that drives various basic functions that are fundamental to cells. Be these protein-protein, protein-nucleic acid or protein-ligand interactions, they all play important roles in a cell. Protein-ligand interactions are the most studied as they can have huge implications in not only understanding the basic mechanism of protein function but also for drug design.
Protein-ligand interactions are governed by several types of weak non-covalent interaction and the thermodynamics associated with these interactions. What weak interactions the ligand makes with the binding site in protein and how... (More)
Molecular recognition is the key aspect of any cellular and biological function. Two or more molecules interacting with each other cause the effects that drives various basic functions that are fundamental to cells. Be these protein-protein, protein-nucleic acid or protein-ligand interactions, they all play important roles in a cell. Protein-ligand interactions are the most studied as they can have huge implications in not only understanding the basic mechanism of protein function but also for drug design.
Protein-ligand interactions are governed by several types of weak non-covalent interaction and the thermodynamics associated with these interactions. What weak interactions the ligand makes with the binding site in protein and how the protein possibly changes conformation to bind ligands are the key to understanding the mechanism involved. One needs structural, thermodynamic and functional data to obtain a complete picture of binding.
To study such interactions one needs a protein target, which is galectin-3 in this case. Galectin-3 is a very well charecterised member of the medically important galectin family. These proteins bind galactose based carbohydrates to exert their function. Their roles in various cellular functions like apoptosis, differentiation, cell-signaling, cell-cell adhesion and immune responses are well documented. They have been implicated in diseases like tumor formation, metastasis and cardiovascular disease which is unsurprising given their involvement in key cellular functions. The need to study their interaction with ligands is an important step towards understanding their function as well as developing drugs against them.
Several methods are used to study these interactions: X-ray crystallography provides an atomic view of the binding, fluorescence polarization provides the binding affinity, isothermal titration calorimetry provides the enthalpic and entropic contributions, neutron crystallography allows us to see hydrogens and thus the hydrogen-bonds involved. Besides these methods, nuclear magnetic resonance and theroretical studies provide energetics of binding. All these methods have been used in this study to provide a complete picture of molecular recognition involved in galectin-3-ligand interactions. The goal was to study basic protein-ligand interactions that can provide insights into designing high affinity and high selectivity inhibitors in the future.
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Abstract (Swedish)
Molecular recognition is the key aspect of any cellular and biological function. Two or more molecules interacting with each other cause the effects that drives various basic functions that are fundamental to cells. Be these protein-protein, protein-nucleic acid or protein-ligand interactions, they all play important roles in a cell. Protein-ligand interactions are the most studied as they can have huge implications in not only understanding the basic mechanism of protein function but also for drug design.
Protein-ligand interactions are governed by several types of weak non-covalent interaction and the thermodynamics associated with these interactions. What weak interactions the ligand makes with the binding site in protein and how... (More)
Molecular recognition is the key aspect of any cellular and biological function. Two or more molecules interacting with each other cause the effects that drives various basic functions that are fundamental to cells. Be these protein-protein, protein-nucleic acid or protein-ligand interactions, they all play important roles in a cell. Protein-ligand interactions are the most studied as they can have huge implications in not only understanding the basic mechanism of protein function but also for drug design.
Protein-ligand interactions are governed by several types of weak non-covalent interaction and the thermodynamics associated with these interactions. What weak interactions the ligand makes with the binding site in protein and how the protein possibly changes conformation to bind ligands are the key to understanding the mechanism involved. One needs structural, thermodynamic and functional data to obtain a complete picture of binding.
To study such interactions one needs a protein target, which is galectin-3 in this case. Galectin-3 is a very well charecterised member of the medically important galectin family. These proteins bind galactose based carbohydrates to exert their function. Their roles in various cellular functions like apoptosis, differentiation, cell-signaling, cell-cell adhesion and immune responses are well documented. They have been implicated in diseases like tumor formation, metastasis and cardiovascular disease which is unsurprising given their involvement in key cellular functions. The need to study their interaction with ligands is an important step towards understanding their function as well as developing drugs against them.
Several methods are used to study these interactions: X-ray crystallography provides an atomic view of the binding, fluorescence polarization provides the binding affinity, isothermal titration calorimetry provides the enthalpic and entropic contributions, neutron crystallography allows us to see hydrogens and thus the hydrogen-bonds involved. Besides these methods, nuclear magnetic resonance and theroretical studies provide energetics of binding. All these methods have been used in this study to provide a complete picture of molecular recognition involved in galectin-3-ligand interactions. The goal was to study basic protein-ligand interactions that can provide insights into designing high affinity and high selectivity inhibitors in the future.
(Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Heine, Andreas, Philipps Universit√§t Marburg
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Protein-ligand interactions, molecular recognition, weak bonds, thermodynamics, enthalpy, entropy, galectin-3, carbohydrate recognition domain, x-ray crystallography, fluorescence polarization, isothermal titration calorimetry, neutron crystallography,
defense location
Lecture hall B, Kemicentrum, Naturvetarvägen 14, Lund
defense date
2019-09-19 13:15:00
ISBN
978-91-7422-683-6
978-91-7422-674-4
language
English
LU publication?
yes
id
dc168873-ec49-43f1-b791-2237c8713a73
date added to LUP
2019-08-25 10:24:09
date last changed
2019-08-27 11:07:35
@phdthesis{dc168873-ec49-43f1-b791-2237c8713a73,
  abstract     = {Molecular recognition is the key aspect of any cellular and biological function. Two or more molecules interacting with each other cause the effects that drives various basic functions that are fundamental to cells. Be these protein-protein, protein-nucleic acid or protein-ligand interactions, they all play important roles in a cell. Protein-ligand interactions are the most studied as they can have huge implications in not only understanding the basic mechanism of protein function but also for drug design. <br/>Protein-ligand interactions are governed by several types of weak non-covalent interaction and the thermodynamics associated with these interactions. What weak interactions the ligand makes with the binding site in protein and how the protein possibly changes conformation to bind ligands are the key to understanding the mechanism involved. One needs structural, thermodynamic and functional data to obtain a complete picture of binding. <br/>To study such interactions one needs a protein target, which is galectin-3 in this case. Galectin-3 is a very well charecterised member of the medically important galectin family. These proteins bind galactose based carbohydrates to exert their function. Their roles in various cellular functions like apoptosis, differentiation, cell-signaling, cell-cell adhesion and immune responses are well documented. They have been implicated in diseases like tumor formation, metastasis and cardiovascular disease which is unsurprising given their involvement in key cellular functions. The need to study their interaction with ligands is an important step towards understanding their function as well as developing drugs against them. <br/>Several methods are used to study these interactions: X-ray crystallography provides an atomic view of the binding, fluorescence polarization provides the binding affinity, isothermal titration calorimetry provides the enthalpic and entropic contributions, neutron crystallography allows us to see hydrogens and thus the hydrogen-bonds involved. Besides these methods, nuclear magnetic resonance and theroretical studies provide energetics of binding. All these methods have been used in this study to provide a complete picture of molecular recognition involved in galectin-3-ligand interactions. The goal was to study basic protein-ligand interactions that can provide insights into designing high affinity and high selectivity inhibitors in the future.<br/>},
  author       = {Kumar, Rohit},
  isbn         = {978-91-7422-683-6},
  language     = {eng},
  month        = {07},
  school       = {Lund University},
  title        = {Structure and energetics of molecular recognition in galectin-3-ligand interactions},
  url          = {https://lup.lub.lu.se/search/ws/files/68792153/opponent_ex_Rohit.pdf},
  year         = {2019},
}