PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Capturing transporter structure paves the way for drug development

Capturing transporter structure paves the way for drug development
2023-05-23
(Press-News.org) (Memphis, Tenn.—May 23, 2023) Scientists at St. Jude Children’s Research Hospital and the University of Texas Southwestern Medical Center studied the structure and function of a transporter involved in cancer and immunity. They captured six structures of the transporter, including when it was bound to an inhibitor, providing unprecedented insight into how it works. The findings, published in Cell, have implications for drug development.  

Transporters escort substances across the cell membrane so that they can carry out their functions. Sphingosine-1-phosphate (S1P) is an important signaling molecule that regulates the immune system, blood vessel formation, auditory function and the integrity of epithelial and endothelial membranes. It aids the progression and survival of cancer cells through chemoresistance and metastasis. 

The S1P molecule is synthesized inside the cell but must cross the cell membrane to carry out its signaling duties. Spinster homolog 2 (Spns2) is an S1P transporter; this protein sits on the membrane and opens toward the inside of the cell, binds to S1P, and then opens toward the outside of the cell to release S1P.   

Research has shown that altering Spns2 activity can have therapeutic effects against cancer, inflammation and immune diseases. However, the transport mechanism of Spns2 and how to inhibit it was unclear.  

“We hope our structural information will pave the way for the development of improved, more specific small molecules with higher potency against Spns2 in the future,” said co-corresponding author Chia-Hsueh Lee, Ph.D., St. Jude Department of Structural Biology. “I think there is huge potential for inhibiting the Spns2 transporter therapeutically.” 

Cryo-EM structures explain how the transporter works 

The researchers obtained six cryo-Electron Microscopy (cryo-EM) structures of Spns2, including two functionally relevant intermediate conformations (shapes) that link the inward (inside a cell) and outward (outside the cell) facing states. The findings reveal the structural basis of the S1P transport cycle.  

“I think these results are quite satisfying because capturing a particular transporter’s major conformations is rare,” Lee added. “By comparing those different structures, we have a very detailed picture of how this transporter captures the S1P signaling molecule.” 

“We used cryo-EM to capture the structure of this transporter and discover how it moves S1P to the outside of the cells,” said co-first author Shahbaz Ahmed, Ph.D., St. Jude Department of Structural Biology. “We also studied an inhibitor and provided the structural data for how it binds the transporter and blocks its activity.” 

The researchers studied how Spns2 binds to the inhibitor 16d, a specific small molecule that has demonstrated very few off-target effects. The researchers found that 16d stops transport activity by locking Spns2 in the inward-facing state. The work aids the development of advanced Spns2 inhibitors.  

“This inhibitor actually blocks the protein in an inward conformation. When the protein is blocked, it cannot transition from inward to outward-facing, and it cannot throw the signaling molecule from inside to outside the cells,” Lee said. “In addition, the inhibitor physically blocks the binding of the signaling molecule because they both bind to the same cavity.” 

Cell surface molecules are an attractive target for drug development. G-protein coupled receptors (GPCRs) are a type of cell surface protein that is the target of one-third of all Food and Drug Administration-approved therapeutics. As cell surface molecules, transporters may have similar potential for drug development. Therefore, understanding their structure and function has the potential to make significant inroads for improving disease treatment.  

“Our work reveals the atomic details of the Spns2-mediated S1P transport cycle, which is important to understanding how this signaling sphingolipid circulates in our immune system,” said co-corresponding author Xiaochun Li, Ph.D., Departments of Molecular Genetics and Biophysics, University of Texas Southwestern Medical Center. “The structures also help the development of potent Spns2 inhibitors, which may contribute to cancer and autoimmune disease treatment.” 

Authors and funding 

The study’s other first authors are Hongwen Chen, University of Texas Southwestern Medical Center, and Hongtu Zhao, St. Jude. Other authors are Nadia Elghobashi-Meinhardt, Technical University Berlin; Jae Hun Kim and Jeffrey McDonald, University of Texas Southwestern Medical Center; and Yaxin Dai, St. Jude. 

The study was supported by grants from the National Institutes of Health (P01HL160487, 1P30DK127984, R01GM134343 and R01GM143282), the Welch Foundation (I-1957), the Damon Runyon Cancer Research Foundation (DRR-53S-19) and ALSAC, the fundraising and awareness organization of St. Jude.  

St. Jude Media Relations Contacts 

 

Chelsea Bryant  
Desk: (901) 595-0564 
Cell: (256) 244-2048 
chelsea.bryant@stjude.org 
media@stjude.org 

 

Emily Gest  

Desk: (901) 595-0260  

Cell: (901) 568-9869  

emily.gest@stjude.org  

media@stjude.org  

  

St. Jude Children's Research Hospital 

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.  

END

[Attachments] See images for this press release:
Capturing transporter structure paves the way for drug development Capturing transporter structure paves the way for drug development 2 Capturing transporter structure paves the way for drug development 3

ELSE PRESS RELEASES FROM THIS DATE:

Did dome-headed dinosaurs sport bristly headgear?

Did dome-headed dinosaurs sport bristly headgear?
2023-05-23
If you look at enough dinosaur fossils, you'll see that their skulls sport an amazing variety of bony ornaments, ranging from the horns of Triceratops and the mohawk-like crests of hadrosaurs to the bumps and knobs covering the head of Tyrannosaurus rex. But paleontologists are increasingly finding evidence that dinosaurs had even more elaborate head ornaments not preserved with the fossil skulls — structures made of keratin, the stuff of fingernails, that were likely used as visual signals or semaphores to others of their kind. A newly described species of dome-headed dinosaur — a pachycephalosaur ...

Lupus Research Alliance and its clinical research affiliate Lupus Therapeutics launch the Lupus Landmark Study to accelerate personalized treatments in lupus

2023-05-23
NEW YORK, NY (May 23) – The Lupus Research Alliance and its clinical research affiliate Lupus Therapeutics today announced the launch of the Lupus Landmark Study, a groundbreaking observational research study to accelerate the development of personalized treatments for people living with lupus. The Lupus Landmark Study, the largest study of its kind in lupus, will prospectively recruit and longitudinally follow 3,500 adults diagnosed with systemic lupus erythematosus (SLE). The Lupus Landmark Study is a ...

The severity of sleep apnea may be underestimated in Black patients

The severity of sleep apnea may be underestimated in Black patients
2023-05-23
Session:  C110, Advanced Signal Analysis: New Diagnostics and Physiologic Insights for SDB (sleep-disordered breathing) Date and Time: 2:15 p.m. ET, Tuesday, May 23, 2023 Location:  WEWCC, Room 144 A-C (Street Level)   ATS 2023, Washington, DC – Obstructive sleep apnea (OSA) tests may underestimate the severity of OSA in Black patients, according to research published at the ATS 2023 International Conference.   Recent research with ICU patients during the COVID-19 pandemic showed that pulse oximeters—clip-like devices that are attached to a fingertip to measure blood oxygen ...

Strategic city planning can help reduce urban heat island effect

2023-05-23
UNIVERSITY PARK, Pa. — The tendency of cities to trap heat — a phenomenon called the “urban heat island,” often referred to as the UHI effect — can lead to dangerous temperatures in the summer months, but new Penn State research suggests that certain urban factors can reduce this effect. The study found that trees had a cooling effect on outdoor air temperature, mean radiant temperature and predicted mean vote index, a measurement designed to evaluate thermal comfort levels. Additionally, the researchers determined that higher building-height-to-street-width ratios — when taller ...

The aging mouse prostate: kinetics of lymphocyte infiltration

The aging mouse prostate: kinetics of lymphocyte infiltration
2023-05-23
“This dataset presents the most comprehensive profiling of the aging adult mouse prostate immune profile to date.” BUFFALO, NY- May 23, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 9, entitled, “Highly multiplexed immune profiling throughout adulthood reveals kinetics of lymphocyte infiltration in the aging mouse prostate.” Aging is a significant risk factor for disease in several tissues, including the prostate. Defining the kinetics ...

Organizations must go beyond medical views on menopause to support women’s professional aspirations - study

2023-05-23
Organisations must enable mid-life women to thrive in the workplace by taking inspiration from societies such as China and Japan to encourage positive conversations around the impact of menopause, a new study reveals. But as they support older women in pursuing their ambitions and accessing career opportunities, organisations must ensure they do not hinder career progression through overlooked promotions, undervalued work, and lost opportunities. In Western countries, the menopause is traditionally viewed as a managed medical condition that creates physiological challenges which women must overcome if they are to function as effectively in the workplace ...

Insomnia drug class may not influence death and exacerbation risks among patients with COPD

Insomnia drug class may not influence death and exacerbation risks among patients with COPD
2023-05-23
Session:  C98, Risky Business: Predicting Consequences of OSA Date and Time: 2:51 p.m. ET, Tuesday, May 23, 2023 Location:  Marriott Marquis Washington, Independence Ballroom, Salons E-H (Level M4)   ATS 2023, Washington, DC – Chronic obstructive pulmonary disease patients newly prescribed non-benzodiazepine benzodiazepine receptor agonists (NBZRAs) such as zolpidem (Ambien, Intermezzo and other brands), a class of hypnotic drugs prescribed for insomnia, did not have an increased risk of exacerbations requiring hospitalizations or of death than those prescribed ...

Researchers treat depression by reversing brain signals traveling the wrong way

2023-05-23
Powerful magnetic pulses applied to the scalp to stimulate the brain can bring fast relief to many severely depressed patients for whom standard treatments have failed. Yet it’s been a mystery exactly how transcranial magnetic stimulation, as the treatment is known, changes the brain to dissipate depression. Now, research led by Stanford Medicine scientists has found that the treatment works by reversing the direction of abnormal brain signals.  The findings also suggest that backward streams of neural activity between key areas of the brain could be used as a biomarker to help diagnose depression. “The leading ...

Strategic habitat restoration can generate a win-win for forests and farmers

Strategic habitat restoration can generate a win-win for forests and farmers
2023-05-23
Carefully planned restoration of agricultural coffee landscapes can increase both farmers’ profit and forest cover over a 40-year period, according to a study publishing May 23rd in the open access journal PLOS Biology by Dr. Sofía López-Cubillos at the University of Queensland in Australia, and colleagues. Restoring patches of natural vegetation in agricultural land presents a trade-off for farmers: while the lost cropland can reduce profitability, increases in ecosystem services like pollination can improve crop yield. To investigate how conservation priorities can be balanced with economic needs, researchers developed a novel planning framework to model the ...

Oxygen restriction helps fast-aging mice live longer

2023-05-23
For the first time, researchers have shown that reduced oxygen intake, or “oxygen restriction”, is associated with longer lifespan in lab mice, highlighting its anti-aging potential. Robert Rogers of Massachusetts General Hospital in Boston, US, and colleagues present these findings in a study publishing May 23rd in the open access journal PLOS Biology. Research efforts to extend healthy lifespan have identified a number of chemical compounds and other interventions that show promising effects in mammalian lab animals— ...

LAST 30 PRESS RELEASES:

Mothers live longer as child mortality declines

Study reveals promising development in cancer-fighting nanotechnologies

Fat cells influence heart health in Chagas disease

C-Path’s TRxA announces its first biologics-focused RFP for academic investigators

Enhancing superconductivity of graphene-calcium superconductors

Federal Trade Commission actions on prescription drugs, 2000-2022

Fluoride exposure during pregnancy linked to increased risk of childhood neurobehavioral problems, study finds

The Ukraine war caused migrating eagles to deviate from their usual flight plan

Endangered migrating eagles impacted by Ukraine war

Study explores association between fluoride exposure in pregnancy and neurobehavioral issues in young children

Using magnetic resonance spectroscopy to design safer, higher-performance lithium batteries

Should your exercise goals be in minutes or steps? Study suggests they are equally beneficial

Racial and ethnic inequities in cancer care continuity during the COVID-19 pandemic among those with SARS-CoV-2

Effect of sleep restriction on adolescent cognition by adiposity

Webb Telescope offers first glimpse of an exoplanet’s interior

Alkyl-aromatic hybrid micelles formed from emergent umbrella-shaped molecules

First study from the African Ancestry Neuroscience Research Initiative identifies key genes in the brain that account for higher rates of some brain disorders in Black Americans

NIH awards Coast-to-Coast Consortium $5.6 million for All of Us Research Program

Ben-Gurion University scientist hunts for drug candidate to treat brain tumors

New Health Blueprint maps healthier future for rural, underserved Southwest Virginia

Survival benefit associated with participation in clinical trials of anticancer drugs

Expanding on the fundamental principles of liquid movement

Chemical Insights Research Institute partners with Duke University and the East-West Center to examine dust and ash from devastating Hawai’ian wildfires

NCCN publishes new resource for patients with intestinal cancer type most have never heard of before diagnosis

Subduction zone splay faults compound hazards of great earthquakes

Record low Antarctic sea ice ‘extremely unlikely’ without climate change

After hundreds of years, study confirms Bermuda now home to cownose rays

Scientists uncover promising treatment target for resistant brain cancer

Revolutionizing cancer treatment by intracellular protein delivery using hybrid nanotubes

Chemist Julian West makes C&EN magazine’s ‘Talented 12’ list

[Press-News.org] Capturing transporter structure paves the way for drug development