Breaking News
May 3, 2019 - Vaping and Smoking May Signal Greater Motivation to Quit
May 3, 2019 - Dementia looks different in brains of Hispanics
May 3, 2019 - Short-Staffed Nursing Homes See Drop In Medicare Ratings
May 3, 2019 - Study of teens with eating disorders explores how substance users differ from non-substance users
May 3, 2019 - Scientists develop new video game that may help in the study of Alzheimer’s
May 3, 2019 - Arc Bio introduces Galileo Pathogen Solution product line at ASM Clinical Virology Symposium
May 3, 2019 - Cornell University study uncovers relationship between starch digestion gene and gut bacteria
May 3, 2019 - How to Safely Use Glucose Meters and Test Strips for Diabetes
May 3, 2019 - Anti-inflammatory drugs ineffective for prevention of Alzheimer’s disease
May 3, 2019 - Study tracks Pennsylvania’s oil and gas waste-disposal practices
May 3, 2019 - Creating a better radiation diagnostic test for astronauts
May 3, 2019 - Vegans are often deficient in these four nutrients
May 3, 2019 - PPDC announces seed grants to develop medical devices for children
May 3, 2019 - Study maps out the frequency and impact of water polo head injuries
May 3, 2019 - Research on Reddit identifies risks associated with unproven treatments for opioid addiction
May 3, 2019 - Good smells may help ease tobacco cravings
May 3, 2019 - Medical financial hardship found to be very common among people in the United States
May 3, 2019 - Researchers develop multimodal system for personalized post-stroke rehabilitation
May 3, 2019 - Study shows significant mortality benefit with CABG over percutaneous coronary intervention
May 3, 2019 - Will gene-editing of human embryos ever be justifiable?
May 3, 2019 - FDA Approves Dengvaxia (dengue vaccine) for the Prevention of Dengue Disease in Endemic Regions
May 3, 2019 - Why Tonsillitis Keeps Coming Back
May 3, 2019 - Fighting the opioid epidemic with data
May 3, 2019 - Maggot sausages may soon be a reality
May 3, 2019 - Deletion of ATDC gene prevents development of pancreatic cancer in mice
May 2, 2019 - Targeted Therapy Promising for Rare Hematologic Cancer
May 2, 2019 - Alzheimer’s disease is a ‘double-prion disorder,’ study shows
May 2, 2019 - Reservoir bugs: How one bacterial menace makes its home in the human stomach
May 2, 2019 - Clinical, Admin Staff From Cardiology Get Sneak Peek at Epic
May 2, 2019 - Depression increases hospital use and mortality in children
May 2, 2019 - Vicon and NOC support CURE International to create first gait lab in Ethiopia
May 2, 2019 - Researchers use 3D printer to make paper organs
May 2, 2019 - Viral infection in utero associated with behavioral abnormalities in offspring
May 2, 2019 - U.S. Teen Opioid Deaths Soaring
May 2, 2019 - Opioid distribution data should be public
May 2, 2019 - In the Spotlight: “I’m learning every single day”
May 2, 2019 - 2019 Schaefer Scholars Announced
May 2, 2019 - Podcast: KHN’s ‘What The Health?’ Bye-Bye, ACA, And Hello ‘Medicare-For-All’?
May 2, 2019 - Study describes new viral molecular evasion mechanism used by cytomegalovirus
May 2, 2019 - SLU study suggests a more equitable way for Medicare reimbursement
May 2, 2019 - Scientists discover first gene involved in lower urinary tract obstruction
May 2, 2019 - Researchers identify 34 genes associated with increased risk of ovarian cancer
May 2, 2019 - Many low-income infants receive formula in the first few days of life, finds study
May 2, 2019 - Global study finds high success rate for hip and knee replacements
May 2, 2019 - Taking depression seriously: What is it?
May 2, 2019 - With Head Injuries Mounting, Will Cities Put Their Feet Down On E-Scooters?
May 2, 2019 - Scientists develop small fluorophores for tracking metabolites in living cells
May 2, 2019 - Study casts new light into how mothers’ and babies’ genes influence birth weight
May 2, 2019 - Researchers uncover new brain mechanisms regulating body weight
May 2, 2019 - Organ-on-chip systems offered to Asia-Pacific regions by Sydney’s AXT
May 2, 2019 - Adoption of new rules drops readmission penalties against safety net hospitals
May 2, 2019 - Kids and teens who consume zero-calorie sweetened beverages do not save calories
May 2, 2019 - Improved procedure for cancer-related erectile dysfunction
May 2, 2019 - Hormone may improve social behavior in autism
May 2, 2019 - Alzheimer’s disease may be caused by infectious proteins called prions
May 2, 2019 - Even Doctors Can’t Navigate Our ‘Broken Health Care System’
May 2, 2019 - Study looks at the impact on criminal persistence of head injuries
May 2, 2019 - Honey ‘as high in sugars as table sugar’
May 2, 2019 - Innovations to U.S. food system could help consumers in choosing healthy foods
May 2, 2019 - FDA Approves Mavyret (glecaprevir and pibrentasvir) as First Treatment for All Genotypes of Hepatitis C in Pediatric Patients
May 2, 2019 - Women underreport prevalence and intensity of their own snoring
May 2, 2019 - Concussion summit focuses on science behind brain injury
May 2, 2019 - Booker’s Argument For Environmental Justice Stays Within The Lines
May 2, 2019 - Cornell research explains increased metastatic cancer risk in diabetics
May 2, 2019 - Mount Sinai study provides fresh insights into cellular pathways that cause cancer
May 2, 2019 - Researchers to study link between prenatal pesticide exposures and childhood ADHD
May 2, 2019 - CoGEN Congress 2019: Speakers’ overviews
May 2, 2019 - A new strategy for managing diabetic macular edema in people with good vision
May 2, 2019 - Sagent Pharmaceuticals Issues Voluntary Nationwide Recall of Ketorolac Tromethamine Injection, USP, 60mg/2mL (30mg per mL) Due to Lack of Sterility Assurance
May 2, 2019 - Screen time associated with behavioral problems in preschoolers
May 2, 2019 - Hormone reduces social impairment in kids with autism | News Center
May 2, 2019 - Researchers synthesize peroxidase-mimicking nanozyme with low cost and superior catalytic activity
May 2, 2019 - Study results of a potential drug to treat Type 2 diabetes in children announced
May 2, 2019 - Multigene test helps doctors to make effective treatment decisions for breast cancer patients
May 2, 2019 - UNC School of Medicine initiative providing unique care to dementia patients
May 2, 2019 - Nestlé Health Science and VHP join forces to launch innovative COPES program for cancer patients
May 2, 2019 - Study examines how our brain generates consciousness and loses it during anesthesia
May 2, 2019 - Transition Support Program May Aid Young Adults With Type 1 Diabetes
May 2, 2019 - Study shows how neutrophils exacerbate atherosclerosis by inducing smooth muscle-cell death
May 2, 2019 - Research reveals complexity of how we make decisions
Scientists define key binding characteristics of protein associated with heart disease and breast cancer

Scientists define key binding characteristics of protein associated with heart disease and breast cancer

Galectins attach to other proteins via the carbohydrates on their surfaces (sugar-binding proteins). As such they impact on a range of processes in the cell associated with a number of diseases, including heart disease and breast cancer – the most common cancer in women worldwide, with 1.7 million new cases diagnosed in 2012 alone.

Hydrogen bonds to lactose in the C-terminal carbohydrate recognition domain of galectin-3 as determined with neutron crystallography. The bonds are represented here by light-blue dotted lines.

Understanding how galectins bind to and distinguish between different sugars can help guide the design of new molecules that act as inhibitors – blocking this process, and therefore limiting the development of certain diseases. However, researchers are only beginning to get the full picture of the binding patterns involved and the exact details of the interactions between different sugars and the protein have not been well defined. Detailed knowledge of the hydrogen bond networks in the protein-sugar complexes is key to providing a better foundation in the efforts to design new effective galectin inhibitors.

In a collaborative effort, experts in neutron and X-ray crystallography from across Europe and the US came together to determine the hydrogen bonding networks in detail for the C-terminal carbohydrate recognition domain of galectin-3 (galectin-3C). Scientists from Institut Laue-Langevin (ILL, France), Lund University (Sweden), Oak Ridge National Laboratory (USA) and Heinz Maier-Leibnitz Zentrum (Germany) all worked together on the project.

Until now, much of our understanding of these binding processes has been guesswork since determining the positions of hydrogen atoms is extremely difficult using X-rays, due to the weak scattering of hydrogen with X-rays. Even in extremely high resolution X-ray crystallography experiments, only about half of the most ordered hydrogen atoms can be observed. Neutron crystallography, on the other hand, is an ideal technique to reveal the positions of hydrogen atoms and hence the geometry of hydrogen bonds, since hydrogen atoms scatter neutrons with approximately the same magnitude as the other elements of a protein (i.e. carbon, nitrogen, oxygen and sulfur). As such, the positions of hydrogen atoms are directly detected with neutrons rather than being inferred from the positions of heavier atoms as in X-ray crystallography.

The resulting paper, published in Journal of Medicinal Chemistry, demonstrates that by using neutron crystallography the positions of the hydrogen atoms and the hydrogen bonding networks can be revealed, providing a better understanding of the binding interactions involved, even at modest resolutions. In addition, by determining the neutron structure of the sugar-free form of galectin-3C (apo galectin-3C) the positions and orientations of water molecules in the binding site before binding have been revealed. Hence comparison of the apo– and sugar-bound structures allowed us to observe how the interactions change upon binding and has helped improve our understanding of the role water plays in the binding process.

Matthew Blakeley, LADI-III beamline scientist at the ILL and co-author of the study, said:

Neutron crystallography is a powerful complementary technique to X-ray crystallography since it provides details relating to hydrogen atom positions which are generally not revealed using X-rays alone. Combining the information from both techniques therefore gives us the most detailed picture possible.”

Derek Logan, associate professor in structural biology at Lund University and main author of the study, said:

This experiment has helped to confirm that drug design against galectins to date has been wise to focus on molecules derived from sugars, as the interactions we see would be difficult to mimic with other molecular shapes. With this confirmation we are now in a much better position to accurately predict the key binding interactions and to help our colleagues in the pharmaceutical industry develop new drugs for use.”

Elucidation of hydrogen bonding patterns in ligand-free, lactose- and glycerol-bound galectin-3C by neutron crystallography to guide drug design, Francesco Manzoni, Johan Wallerstein, Tobias Schrader, Andreas Ostermann, Leighton Coates, Mikael Akke, Matthew P. Blakeley, Esko Oksanen and Derek T. Logan [doi: 10.1021/acs.jmedchem.8b00081]

Source:

https://www.ill.eu/news-press-events/press-corner/press-releases/first-study-of-galectin-proteins-with-neutrons-guiding-future-drug-development/

Tagged with:

About author

Related Articles