Breaking News
November 14, 2018 - Health Tip: Limit Fat, Sugar and Salt in Your Child’s Diet
November 14, 2018 - CA 19-9 Blood Test (Pancreatic Cancer): MedlinePlus Lab Test Information
November 14, 2018 - Old drug could have new use helping sick premature babies
November 14, 2018 - Surgery, not antibiotics, should remain first-line treatment for appendicitis | News Center
November 14, 2018 - Researchers to develop sports-specific classification system for blind football
November 14, 2018 - Preschool children show awake responses to naptime nonsense words
November 14, 2018 - Survey shows negative effect of vulvovaginal atrophy symptoms on quality of life for women
November 14, 2018 - Study sheds light on mechanisms that prevent autoimmune attack
November 14, 2018 - Sleep quality found to be worse for women who undergo surgical menopause
November 14, 2018 - New study provides deeper insight into chromosome segregation during mitosis
November 14, 2018 - Inhibition of one protein clears toxic clumps seen in Parkinson’s disease, study finds
November 14, 2018 - Appendix removal is linked to lower risk of Parkinson’s
November 14, 2018 - Lifting weights for less than an hour a week may reduce cardiovascular disease risk
November 14, 2018 - Pulmonary rehabilitation rarely received by hospitalized COPD patients despite health benefits
November 14, 2018 - New anti-HER2 drug shows promising anti-tumor activity in gullet, stomach and bowel cancers
November 14, 2018 - Regular head circumference assessment of preterm babies can help identify long-term IQ problems
November 14, 2018 - Brigham investigators examine opioid use among Massachusetts adolescents, prescription trends
November 14, 2018 - Study defines biomarker in response to treatment of castration-resistant prostate cancer
November 14, 2018 - Study identifies potential therapeutic strategy for patients with clear cell renal cancer
November 14, 2018 - Bausch Health Announces U.S. Launch of Bryhali (halobetasol propionate) Lotion, 0.01%, for Plaque Psoriasis In Adults
November 14, 2018 - Alpha Fetoprotein (AFP) Tumor Marker Test: MedlinePlus Lab Test Information
November 14, 2018 - Researchers evaluate controversial treatment for Parkinson’s disease psychosis
November 14, 2018 - AI could help veterinarians code their notes
November 14, 2018 - Pre-schoolers with autism thrive in mainstream classroom settings
November 14, 2018 - Individual and work-related factors may help promote hospital physician engagement, finds study
November 14, 2018 - Complementary and alternative medicine is widely used by general population in England
November 14, 2018 - Study reveals link between tobacco availability and smoking during pregnancy
November 14, 2018 - Purdue researchers develop translucent base for silicon patches to deliver exact doses of biomolecules
November 14, 2018 - New technology based on moths and magnets could help treat genetic diseases
November 14, 2018 - Concussion-Related Biomarkers Vary Based on Sex, Race
November 14, 2018 - One more year of high school may shape waistlines later in life
November 14, 2018 - Dissecting high drug costs – Scope
November 14, 2018 - Study shows novel strategy to reduce breast cancer bone metastasis
November 14, 2018 - Empowering the NHS through Industry Partnerships
November 14, 2018 - One size does not fit all in obesity treatment, study finds
November 14, 2018 - Seeking ways to prevent ‘secondary cataracts’
November 14, 2018 - Change Within the Eye May Be Early Warning for Macular Degeneration
November 14, 2018 - Study of 500,000 people clarifies the risks of obesity
November 14, 2018 - Ultrasound releases drug to alter activity in targeted brain areas in rats | News Center
November 14, 2018 - Umass Amherst researchers battle against youth suicide in rural Alaska Native communities
November 14, 2018 - Cancer stem cells depend on amino acid metabolism, and it’s proving to be their Achilles’ heel
November 14, 2018 - Epigenetic link found between prenatal exposure to maternal smoking and offspring’s cardio-metabolic health
November 14, 2018 - Meditation, music may change biomarkers of cellular aging and Alzheimer’s disease in older adults
November 14, 2018 - Multidisciplinaryresearch teams selected to study age-related brain disorders
November 14, 2018 - The Current issue of “The view from here” is concerned with Informatics
November 14, 2018 - Researchers identify tool to help transgender women have a more authentic voice
November 14, 2018 - Four faculty members appointed to endowed professorships | News Center
November 13, 2018 - Research finds strongest evidence yet that obesity causes depression
November 13, 2018 - Researchers compare stools of breastfed and formula-fed infants
November 13, 2018 - Entasis Therapeutics Announces Zoliflodacin Phase 2 Results Published in The New England Journal of Medicine
November 13, 2018 - Gene changes driving myopia reveal new focus for drug development
November 13, 2018 - $6 million grant to support study of preeclampsia, atherosclerosis links | News Center
November 13, 2018 - Beneficial gut microbes metabolize high-fiber diet to improve heart health in mouse model
November 13, 2018 - Excessive use of social media through visual postings linked to increase in narcissistic traits
November 13, 2018 - Study finds why obesity both fuels cancer growth and helps immunotherapy to kill tumors
November 13, 2018 - Women prefer and invest more in daughters, while men favor sons
November 13, 2018 - With hospitalization losing favor, judges order outpatient mental health treatment
November 13, 2018 - Transgenic rat model may provide new insights into cerebral amyloid angiopathy
November 13, 2018 - Study identifies factors tied to greater risk of advanced liver disease in cystic fibrosis patients
November 13, 2018 - Risk of blindness among premature babies with low levels of blood platelets
November 13, 2018 - A new strategy for combatting antibiotic-resistant infections
November 13, 2018 - Study aims to find which outreach method is more effective at improving cancer screening rates
November 13, 2018 - Insufficient sleep duration linked with unhealthy lifestyle profile among children
November 13, 2018 - IIASA researchers introduce new, simple measure for human wellbeing
November 13, 2018 - Magnetic nanosprings used as targeted drug delivery agents for anticancer therapy
November 13, 2018 - Scientists examine FCMs containing silver nanoparticles
November 13, 2018 - Failed DNA repair triggers chromosomal chaos
November 13, 2018 - Study shows new emerging role of osteopontin in HCV-related hepatocellular carcinoma
November 13, 2018 - Food insecurity during pregnancy linked to severity of neonatal abstinence syndrome
November 13, 2018 - Majority of Americans are concerned about health threat posed by antibiotic resistance
November 13, 2018 - Addition of Elotuzumab Ups PFS in Refractory Multiple Myeloma
November 13, 2018 - Study finds women with pregnancy-related nausea, vomiting use marijuana more
November 13, 2018 - Lethal heart rhythm more likely to be found in patients with common heart failure
November 13, 2018 - Study provides new clues to origin and development of multiple sclerosis
November 13, 2018 - Climate change could pose threat to male fertility
November 13, 2018 - Researchers discover how mitochondria deploy a powerful punch against disease-causing bacteria
November 13, 2018 - AHA: Traumatic Childhood Could Increase Heart Disease Risk in Adulthood
November 13, 2018 - Feeling the Burn? | NIH News in Health
November 13, 2018 - Women’s birth canals in Kenya, Korea, Kansas not the same: study
November 13, 2018 - Fecal microbiota transplantation effective against ICI-associated colitis

Molecular details of protein crystal nucleation uncovered

image_pdfDownload PDFimage_print

Dr. Mike Sleutel (VIB-VUB): “It will be exciting to see this new technique being applied in the future to follow protein self-assembly processes that are implicated in a range of pathological disorders, such as liquid-liquid phase separation in eye cataract formation or the formation of amyloid fibers associated with a range of neurological disorders.” The Nature article can be accessed here.

 

Medical importance of protein crystals

Protein crystals bear great medical and scientific relevance. For decades, they have been essential for structural biologists to solve the three-dimensional structures of proteins, but protein crystals are also used as bio-pharmaceutical delivery agents. Crystalline suspensions are attractive formulations to store and administer active pharmaceutical compounds because of their long-term shelf life, low solvent viscosity, and slow dissolution rate. Perhaps the best known example is insulin: insulin shots comprise the subcutaneous injection of a suspension of insulin microcrystals which dissolve slowly to yield a steady and sustained delivery over time. Despite their tremendous potential, there are two factors that limit the use of protein crystals in a broad range of applications.

 

Challenges in developing protein crystals

First, growing protein crystals, as many molecular biologists will say, is more an art than a science. In fact, for many proteins, crystallization can be excruciatingly difficult. This in part follows from the fact that scientists don’t understand the early stages of protein crystal formation. Any crystal originates from a nucleus, a tiny crystalline seed, which forms by the spontaneous grouping of a few molecules in solution that have to adopt a regular organization in three-dimensions. How the molecules realize this improbable feat has remained a mystery up until this point.

Secondly, a single protein can crystallize in multiple different crystal forms, this is known as polymorphism. Different crystal polymorphs have different characteristics, with the most notable ones the power to diffract X-rays (crucial for 3D structure determination), and the rate at which it dissolves (crucial for drug delivery). As of yet, it is very difficult to guide the crystallization process to the polymorph of one’s liking. Scientists believe that polymorph selection takes place at the stage of nucleation, but no one knows exactly how the mechanism works.

 

A new way to look at the self-assembly of macromolecules

The group of scientists lead by Dr. Mike Sleutel have used state-of-the-art cryo-transmission electron microscopy (Cryo-TEM) to capture the birth of a protein crystal by visualizing the process of nucleation at molecular resolution.

Dr. Heiner Friedrich explains: “Because the process happens so rapidly, and at such a small length scale we needed to cryogenically arrest the sample at various stages of the process. Once frozen in time, we use a very sensitive electron microscope to visualize the proteins and how they group together to form a nucleus and finally the protein crystal.”

By analyzing the Cryo-TEM images taken from a series of samples at constant time intervals, they could start to puzzle together the series of molecular collisions that need to take place to form a crystalline nucleus. Dr. Mike Sleutel continues: “We were struck by the unexpected complexity of the process, which proved to be far more intricate than the working models we and other in the field had prior to these observations. For the protein that we used in our study we uncovered a hierarchical self-assembly process that involves three subsequent stages of self-assembly at ever increasing length scales.” These observations are the first of their kind and provide an new way to look at the self-assembly processes of macromolecules into larger structures.

But the team went even one step further, and compared the nucleation pathways of multiple polymorphs. They showed that polymorph selection is dictated by the architecture of the smallest possible fragments formed at early time-points. Once such structures are formed, the faith of the system is set. Dr. Alexander Van Driessche explains: “By analyzing and understanding the differences in structure of the various nuclei, we developed strategies to guide the polymorph selection process. We achieved this by gently tweaking the different modes of interaction that exist between the molecules, steering the nucleation process in the direction of our choosing.” The team believes that the new insights and methodology will significantly advance the development of protein crystals for 3D structure determination and medical applications.

Dr. Mike Sleutel works in the Han Remaut lab in the VIB-VUB Center for Structural Biology

Tagged with:

About author

Related Articles