Computational analysis of long-range allosteric communications in CFTR

Ayca Ersoy, Bengi Altintel, Nurit Livnat Levanon, Nir Ben-Tal, Turkan Haliloglu*, Oded Lewinson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Malfunction of the CFTR protein results in cystic fibrosis, one of the most common hereditary diseases. CFTR functions as an anion channel, the gating of which is controlled by longrange allosteric communications. Allostery also has direct bearings on CF treatment: the most effective CFTR drugs modulate its activity allosterically. Herein, we integrated Gaussian network model, transfer entropy, and anisotropic normal mode-Langevin dynamics and investigated the allosteric communications network of CFTR. The results are in remarkable agreement with experimental observations and mutational analysis and provide extensive novel insight. We identified residues that serve as pivotal allosteric sources and transducers, many of which correspond to diseasecausing mutations. We find that in the ATP-free form, dynamic fluctuations of the residues that comprise the ATP-binding sites facilitate the initial binding of the nucleotide. Subsequent binding of ATP then brings to the fore and focuses on dynamic fluctuations that were present in a latent and diffuse form in the absence of ATP. We demonstrate that drugs that potentiate CFTR’s conductance do so not by directly acting on the gating residues, but rather by mimicking the allosteric signal sent by the ATP-binding sites. We have also uncovered a previously undiscovered allosteric ‘hotspot’ located proximal to the docking site of the phosphorylated regulatory (R) domain, thereby establishing a molecular foundation for its phosphorylation-dependent excitatory role. This study unveils the molecular underpinnings of allosteric connectivity within CFTR and highlights a novel allosteric ‘hotspot’ that could serve as a promising target for the development of novel therapeutic interventions.

Original languageEnglish
Article numberRP88659
StatePublished - Dec 2023


FundersFunder number
Israeli Academy of Sciences1006/18
NATO Science for Peace and Security Program
Saudi Pharmaceutical SocietyG5685
Türkiye Bilimsel ve Teknolojik Araştırma Kurumu119F392


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