Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Corradi, Valentina; Vergani, Paola; Tieleman, D. Peter

doi:10.1074/jbc.m115.665125

Cited by 49 publications

(66 citation statements)

References 113 publications

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“…Since both conformations are compatible with some functional data, we presume that both types of conformations possess physiological features, but represent short-living conformations under physiological conditions. Similar to Corradi et al [17] we suggest that the conducting conformation is similar to that of McjD with TM helices close to each other both at the bottom and the top (Fig. 4 c).…”

Section: Discussionsupporting

confidence: 91%

“…In order to further test the probability of the bottom-open CFTR conformation, we performed similar simulations with the inward-facing, bottom-closed apo CFTR TM287/288 model [17]. In two out of six simulations the distance between the NBDs increased and approximated the value observed in the zfCFTR structure, with no contacts between the two domains (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Zebrafish and human CFTR structures derived from EM maps were downloaded from the PDB database: (PDBIDs: 5TSI/5UAR, 5U71/5UAK) [15,16]. We also employed the CFTR homology models generated by Corradi et al based on the TM287/288, McjD, and Sav1866 templates [17]. We call these models as CFTR TM287/288 , CFTR MCJD , and CFTR SAV1866 , respectively.…”

Section: Methodsmentioning

confidence: 99%

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Molecular dynamics of the cryo-EM CFTR structure

Tordai

Leveles

Hegedüs

2017

Biochemical and Biophysical Research Communications

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Cystic fibrosis (CF), a lethal monogenic disease, is caused by mutant variants of the CF transmembrane conductance regulator (CFTR). Recent advances in single molecule cryo-EM methods enabled structural determination of full-length human and zebrafish CFTR, achieving an important milestone for CF drug development. To relate these structures to the gating cycle, we examined its dynamic features using molecular dynamics simulations. Our results show that the nucleotide binding domains (NBDs) in this bottom-open apo conformation exhibit motions related to dimerization and the bottom-closed apo CFTR model indicates opening of NBDs in contrast to transporters. These observations help in understanding the properties of CFTR chloride channel distinct from transporters and in proper interpretation of available structural information on this ABC protein.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

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Molecular dynamics of the cryo-EM CFTR structure

Tordai

Leveles

Hegedüs

2017

Biochemical and Biophysical Research Communications

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“…The outward facing models 14,[17][18][19][20][21][22][23] were based primarily on the Sav1866 structure as a template, 24 although recently the newly solved ABC transporter structure McjD 25 has been used to model this state. 26 Inward facing models were based either on the bacterial MsbA 27 or on the P-gp 28 structures. However, new CFTR models of this state were recently reported, based on the structures of the ABC transporters TM287/288 29 and ABCB10.…”

Section: Introduction Cystic Fibrosis (Cf) Is a Lethal Inherited Dismentioning

confidence: 99%

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Simhaev

McCarty

Ford

et al. 2017

J. Chem. Inf. Model.

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Cystic Fibrosis (CF) is a lethal, genetic disease found in particular in humans of European origin which is caused by mutations in the CFTR chloride channel. The search for CF therapies acting by modulating the impaired function of mutant CFTR will be greatly advanced by high resolution structures of CFTR in different states. To date, two medium resolution EM structures of CFTR are available (one of a distant zebrafish (Danio rerio) CFTR ortholog and one of human CFTR). The two models are nearly identical to one another and both correspond to the inward-facing, NBDs separated, closed state of the channel. In addition, lower resolution structural data are available for human CFTR in an alternative conformation which likely features associated NBDs and thus geometrically resembles the conducting state of the channel.Multiple homology models of human CFTR in multiple states have been developed over the years, yet their correspondence to the existing structural information is unexplored. In this work we use molecular dynamics flexible fitting (MDFF) simulations to refine two previously described CFTR models based on the available cryo-EM map of the human protein. This map was recorded in the absence of ATP and consequently represents closed-state CFTR yet its features likely correspond to a NBDs associated conformation of the protein. Accordingly, the resulting models feature dimerized NBDs yet with no membrane traversing pore. Moreover, the open probability of the new models as deduced from the MDFF trajectories is significantly lower than that deduced from control MD trajectories initiated from the starting models. We propose that the new models correspond to a CFTR conformation which to date was largely unexplored yet one that is relevant to the gating cycle of the protein. In particular this conformation may participate in rapid channel opening and closing through small allosteric movements controlled by nucleotide binding and dissociation events. Analyzing the resulting trajectories (and not only the final models as is usually the case), we demonstrate that the refined models have good stereochemical properties and are also in favorable agreement with multiple experimental data.Moreover, despite different starting points, the final models share many common features.Finally, we propose that the combination of high resolution cryo-EM maps which are currently emerging from multiple labs and MDFF simulations will be of value for the development of yet more reliable CFTR models as well as for the identification of binding sites for CFTR modulators.

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“…In 2002, Martinoia et al [27] found that ABC transporters in plants showed related structures with no related functions. On the other hand, apart from function, [11] suggested structurer comparison using fitted models as mentioned before. A similar issue was reported by [33].…”

Section: Disccusionmentioning

confidence: 99%

Untitled

2016

RJLBPCS

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Cystic fibrosis (CF) is an inherited disorder that affects about one out of every 3,000 newborns and causes a loss of transport channel activity in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Up to date, no solved structure of CFTR and this due to the difficulty of expressing, purifying and crystallizing of transmembrane proteins. In this study, structural and functional properties of solved structure ABC transporters in comparison to human CFTR were investigated using several Bioinformatics tools. Phylogenetic analysis showed that CFTR clusters withMcjD, PglK and Atm1 in one lineage and they might share the same genetic origin. Alignment results revealed that NBD2 of CFTR contained several conserved amino acids (small fragments with no more 7 following residues) while NBD1 was the only completely shared domain. As a one-to-one protein comparison, ABCB1 and Pgp (known as permeability glycoproteins) showed the closest biophysical and biochemical properties to CFTR. These properties include secondary structures, sequence length, isoelectric point, GRAVY index, coiled coils, longest disorder region and the number of transmembrane helices. Based on model fitting analysis, outward facing Sav1866 and MsbA were fitted with the highest correlation coefficients (0.49 and 0.47, respectfully). A homology model of CFTR was built based on McjD, ABCB1 and Sav1866. The model showed a significant similarity to ABCB1.

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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Cited by 49 publications

References 113 publications

Molecular dynamics of the cryo-EM CFTR structure

Molecular dynamics of the cryo-EM CFTR structure

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

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