3D rendering of CFTR protein

Unlocking CFTR: How New 3D Structures are Changing Cystic Fibrosis Research

Lena Voss in Health & Wellness August 2025 • 4 min read.

"Recent breakthroughs in understanding the CFTR protein offer hope for improved therapies and a deeper understanding of cystic fibrosis."

Cystic fibrosis (CF) is a devastating genetic disorder affecting thousands worldwide. At the heart of this disease lies the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a crucial component for regulating the flow of salt and water across cell membranes. When CFTR malfunctions, it leads to a buildup of thick mucus in the lungs, digestive system, and other organs, causing a range of life-threatening complications.

For years, scientists have been working tirelessly to unravel the complexities of the CFTR protein. Understanding its structure is key to deciphering how it works, how mutations disrupt its function, and how we can develop effective therapies. Now, thanks to recent advances in structural biology, we're finally gaining unprecedented insights into the 3D architecture of CFTR.

This article delves into the latest breakthroughs in CFTR structural research, summarizing the recent progress in understanding its 3D structure and briefly discussing the implications for developing new treatments. We'll explore how these findings are transforming our understanding of CF and offering new hope for improved therapies.

A 3D Revolution: Mapping the CFTR Protein

The journey to understanding CFTR's structure has been a long and challenging one. Researchers have spent years studying individual domains of the protein using techniques like X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. However, obtaining a complete picture of the full-length protein proved difficult due to its instability and dynamic nature.

One major hurdle was producing stable constructs of the nucleotide-binding domains (NBDs), particularly NBD2. Recent progress has been made in identifying stabilizing mutations in NBD2, which opens new avenues for studying NBD-NBD interactions. Despite these challenges, scientists persevered, employing techniques like cryo-electron microscopy (cryo-EM) and comparative modeling to piece together the puzzle.

Cryo-EM Breakthrough: Recent studies utilizing cryo-EM have provided medium-to-high-resolution 3D structures of the full-length CFTR protein.
Zebrafish and Human CFTR: Structures have been obtained from both zebrafish and human CFTR, offering valuable insights into the protein's architecture.
Inactive State Structures: These initial structures represent a non-phosphorylated, apo form of the channel, depicting a closed and inactive state. The nucleotide-binding domains (NBDs) are fully dissociated in this conformation.

These 3D structures have revealed crucial details about CFTR's architecture, including the arrangement of its membrane-spanning domains (MSDs) and the interactions between different regions of the protein. While the initial structures represent an inactive state of the channel, they provide a foundation for understanding the conformational changes that occur during channel gating. Furthermore, these structures have confirmed the existence of a newly described N-terminal "lasso," which interacts with the transmembrane helices.

The Future of CFTR Research and Therapy

The recent advances in CFTR structural biology represent a major step forward in our understanding of cystic fibrosis. These new 3D structures provide a framework for deciphering the molecular mechanisms underlying channel gating, drug interactions, and the effects of disease-causing mutations.

While significant progress has been made, many questions remain. Future research will focus on obtaining higher resolution structures, characterizing the conformational changes that occur during channel gating, and elucidating the mechanisms of action of current modulator compounds. Understanding the role of the R region in regulating channel activity is also a key area of investigation.

Ultimately, these structural insights will pave the way for the development of more effective therapies for cystic fibrosis. By understanding the intricate details of CFTR's structure and function, scientists can design targeted drugs that correct the underlying defects and improve the lives of individuals living with this challenging disease.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.jcf.2017.08.008, Alternate LINK

Title: Cftr Structure

Subject: Pulmonary and Respiratory Medicine

Journal: Journal of Cystic Fibrosis

Publisher: Elsevier BV

Authors: Isabelle Callebaut, P. Andrew Chong, Julie D. Forman-Kay

Published: 2018-03-01

Everything You Need To Know

What is the role of the CFTR protein in the context of cystic fibrosis?

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is critical for regulating salt and water flow across cell membranes. In cystic fibrosis, a malfunction of CFTR leads to thick mucus buildup in organs like the lungs and digestive system, causing severe complications. Understanding the CFTR protein's structure is essential for deciphering its function and developing effective therapies. Further research is needed to completely understand how CFTR interacts with other cellular components and how its dysfunction affects various organ systems, paving the way for more targeted treatments.

How have recent advancements in structural biology contributed to understanding CFTR?

Recent breakthroughs using techniques like cryo-electron microscopy (cryo-EM) have provided medium-to-high-resolution 3D structures of the full-length CFTR protein. These structures, obtained from both zebrafish and human CFTR, offer valuable insights into the protein's architecture. While these initial structures represent an inactive state of the channel, they provide a foundation for understanding the conformational changes that occur during channel gating and the effects of disease-causing mutations.

What challenges did researchers face while trying to determine the 3D structure of the CFTR protein, and how were they overcome?

Researchers faced several hurdles in determining the 3D structure of CFTR, including the protein's instability and dynamic nature, which made it difficult to obtain a complete picture of the full-length protein. One major challenge was producing stable constructs of the nucleotide-binding domains (NBDs), particularly NBD2. Progress has been made in identifying stabilizing mutations in NBD2, opening new avenues for studying NBD-NBD interactions. Scientists used techniques like cryo-electron microscopy (cryo-EM) and comparative modeling to piece together the puzzle.

What are the implications of the newly discovered N-terminal 'lasso' in the CFTR protein structure?

The confirmation of the N-terminal 'lasso' interacting with transmembrane helices is a significant finding in CFTR structural biology. This lasso likely plays a role in the protein's folding, stability, or gating mechanism. Further research is needed to fully understand its function, but it offers a new target for therapeutic interventions. Future studies may explore how mutations in or near the N-terminal 'lasso' affect CFTR function and contribute to disease severity, opening potential avenues for drug development.

How do these new 3D structures of CFTR help in developing new treatments for cystic fibrosis?

The new 3D structures of CFTR provide a framework for understanding the molecular mechanisms behind channel gating, drug interactions, and the effects of disease-causing mutations. By visualizing the protein's architecture, scientists can design therapies that target specific regions or correct structural defects. This knowledge can lead to the development of more effective drugs that restore CFTR function and alleviate the symptoms of cystic fibrosis. Understanding how different drugs bind to CFTR and affect its function can lead to more personalized and effective treatment strategies.