Ortholog conservation:

The wild-type residue I1051 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs)
The variant I1051F has never been found among the CFTR orthologs

*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1051). AAPIR appears in green if it is more than 10% compared to AAPI, in red if less than 10%.
Click here for more details on the alignment.

CYSMA's visualizing modules for Ortholog conservation:

⬇ Download the region alignment (50 residues, Fasta format)
⬇ Download the CFTR phylogenic tree

Display methods

Domain conservation:

The residue p.Ile1051 belongs to the domain MSD2.

844

1203

MSD2: is the membrane-spanning domain 2, composed of six transmembrane helices (TM7-TM12).
Four of the six TMs protrude into the cytosol to form the intracellular loops. ICL3 (between TM8 and TM9) and ICL4 (between TM10 and TM11). ICL3 contacts the NBD2 at the level of the ATP-binding site, while ICL4 binds in a groove located at the surface of NBD1.

	is the membrane-spanning domain 2, composed of six transmembrane helices (TM7-TM12). Four of the six TMs protrude into the cytosol to form the intracellular loops. ICL3 (between TM8 and TM9) and ICL4 (between TM10 and TM11). ICL3 contacts the NBD2 at the level of the ATP-binding site, while ICL4 binds in a groove located at the surface of NBD1.

MSD2 of CF Transmembrane conductance Regulator domain alignment including p.Ile1051 residue.

***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
^!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1051). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.

The wild-type residue I1051 belongs to the MSD2 domain and is conserved at 62.20% among the MSD2 homologs (79 / 127 MSD2 homologs)
The variant I1051F has been found among the MSD2 homologs with a non significant frequency: 2.36% (3 / 127 MSD2 homologs)

Divergencies show the amino acids which have been selected in the evolution. Residues present in more than 10% of the sequences are highlighted in blue.
Please note that CYSMA does not consider splicing alterations.
Refer to the Help page for more details.

CYSMA's visualizing modules for MSD2 domain conservation:

Display methods

Secondary structure analysis:

Residue p.Ile1051 is predicted to belong to an α helice. Probability is 0.698.

Direct environment is as follow:

G	R	S	P	I1051	F	T	H	L

Observed frequencies in α helices:
I: 0.99
F: 0.97

The two residues are found equivalent in this type of structure.

Display methods

3D analysis:

Models provided and analysed by CYSMA must be considered as predictions, therefore be careful when interpreting the results. All efforts have been made to build structures of quality, however, they are provided with NO WARRANTY as to their accuracy with the real biological molecules studied.

Wild type and predicted mutant structures have been compared. You will find the results below.

• Overall quality of the structure:
  
  

  PDB template	Sequence identity*	MolProbity bad rotamers	MolProbity Ramachandran outliers	MolProbity Ramachandran favored
  5UAK	99.8 %	18/1313 - 1.37 %	17/1474 - 1.15 %	1360/1478 - 92.2 %

  
  
  

• Click on the MolProbity logo for complete details on the structure quality
  
  
  
  

• This model is made of 37 α helices and of 20 β strands (and is mainly composed of helices (739 residues in helices against 102 in strands, for a total of 1480 amino acids)).
  
  
• 3D structures predicts I1051 to be located in an α helice (which confirms PsiPred prediction) and F1051 in an α helice.
  Moreover, the residue is located in the core of this α helice (which contains 56 residues).
  Helix interior propensities of wild-type and mutant residues are 1.3 and 1.06.
  
  



CYSMA's modules to download the 3D structures:



Chech 3D coverage of CFTR models ⬇ Download the wild-type 3D structure (PDB format) ⬇ Download the mutant 3D model (PDB format)





CYSMA's 3D Automatic Annotation:





WARNING!
The experimental 3D structure used for our predictions is the complete human CFTR structure which have been solved at a 3.7 Å resolution using cryo-electron microscopy (PDB: 5UAK; Liu et al. 2017).
The overall resolution is fairly low so the CYSMA's 3D Automatic Annotation pipeline might have missed some important structural effects.




• Solvent accessibility: the wild-type I1051 and the mutant I1051F are predicted to be buried
  
  
• Hydrogen bond network:
  

  I1051	F1051
  none	none

  
  
  
• The mutant residue is predicted to form comparable hydrophobic interactions than the wild-type
  The wild-type residue ILE is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is maintained in the mutant residue PHE
  
  

  I1051

  F1051

  4.52 Å between ILE 1051 CG1 and LEU 1082 CD2 4.82 Å between ILE 1051 CG2 and LEU 1082 CD2 4.95 Å between ILE 1051 CD1 and LEU 1082 CG 4.66 Å between ILE 1051 CB and PHE 1052 CD1 4.85 Å between ILE 1051 CG2 and PHE 1052 CD1 4.53 Å between ILE 1051 CB and ALA 1081 CB 3.69 Å between ILE 1051 CG1 and ALA 1081 CB 4.84 Å between ILE 1051 CD1 and ALA 1081 CB 4.35 Å between ILE 1051 CD1 and HIS 1085 CG 4.92 Å between ILE 1051 CB and PHE 1078 CE1 4.85 Å between ILE 1051 CG2 and PHE 1078 CD1

  4.22 Å between PHE 1051 CE1 and PHE 157 CB 5.00 Å between PHE 1051 CE2 and PHE 157 CB 3.87 Å between PHE 1051 CZ and PHE 157 CB 4.95 Å between PHE 1051 CG and LEU 1082 CD2 4.70 Å between PHE 1051 CD1 and LEU 1082 CG 4.26 Å between PHE 1051 CE1 and LEU 1082 CG 4.11 Å between PHE 1051 CZ and LEU 1082 CD2 4.89 Å between PHE 1051 CB and PHE 1052 CG 4.89 Å between PHE 1051 CG and PHE 1052 CD1 4.83 Å between PHE 1051 CD2 and PHE 1052 CG 4.77 Å between PHE 1051 CD2 and LEU 184 CG 4.93 Å between PHE 1051 CE1 and LEU 184 CD2 3.98 Å between PHE 1051 CE2 and LEU 184 CG 4.45 Å between PHE 1051 CZ and LEU 184 CG 4.81 Å between PHE 1051 CD2 and LEU 1055 CB 4.85 Å between PHE 1051 CE2 and LEU 1055 CB 4.78 Å between PHE 1051 CZ and LEU 1055 CD1 4.79 Å between PHE 1051 CG and PHE 1078 CE1 4.55 Å between PHE 1051 CD1 and PHE 1078 CE1 4.60 Å between PHE 1051 CD2 and PHE 1078 CE1 4.12 Å between PHE 1051 CE1 and PHE 1078 CE1 4.18 Å between PHE 1051 CE2 and PHE 1078 CE1 3.92 Å between PHE 1051 CZ and PHE 1078 CE1

  
  
  

For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.



• The mutant residue might introduce steric clashes
  

  I1051	F1051
  none	3.04 Å between PHE 1051 CE1 and LEU 1082 CD2 2.91 Å between PHE 1051 CB and PHE 1052 N 3.07 Å between PHE 1051 CE2 and LEU 184 CD1

  
  
  

CYSMA's 3D visualizing module:



• If you want to investigate further the structures, you can use the JSmol applets of the wild-type (left) and mutant (right) structures.
  
  Click on the JSmol applets' link to hide it.
  You have a full access to Jmol commands with a simple right click on one applet.
  
  
  
  
  

  I1051 (wild-type)	F1051 (mutant)

  
                Slab       Spin on/off       Show measurements       Change background       Sharper/Faster                    

  
  JSmol Legends:
  The residue at the position 1051 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å).
  Van der Waals contacts with the residue 1051 are represented by dotted lines.
  Amino acids involved in H-bonds with the residue 1051 are labelled in blue.
  Amino acids involved in steric clashes with the residue 1051 are labelled in red.

  
  Display JSmol complete legends

  The overall structure of the complete human CFTR is represented in ribbon diagrams (click on the Reset button to visualize the overall CFTR structure).
  The membrane-spanning domain MSD1 is represented in blue and MSD2 in light blue.The nucleotide-binding domain NBD1 is represented in orange, NBD2 in light salmon.The lasso domain is shown in red and the R domain in green.

  Display Molecular Modelling methods

  The 3D structures used in CYSMA are models based on the CFTR experimental 3D structure in the channel-closed conformation (PDB: 5UAK; resolution: 3.9 Å).
  In the wild-type model, the (missing) loops and the (missing) R domain were built de novo using the software Modeller. For the variant models, the point mutation (homology modelling) are made on the fly with Modeller (more). Each structure has been assessed with MolProbity⁽¹⁹⁾. Msms⁽²⁰⁾ is used to calculate solvent accessibility, and STRIDE⁽²¹⁾ (plus stride2pdb) for secondary structure assignment.
  Secondary structure analyses in 3D models uses side chain interaction energies reviewed in ⁽²³⁾, as well as amino-acids propensities for N-caps, N1-N3, helix middle, C3-C1 and C-caps extracted from ⁽²⁴⁾(PDB values).
  Structural properties are calculated using an in-house developped program based for the USMA's 3D Automatic Annotation pipeline.

  Refer to the Help page for more details.

• SIFT prediction: variant I1051F is predicted to be damaging (score: 0.01)


• PPH2 prediction: variant I1051F is predicted to be damaging (score: 1)


• UNIPROT annotations
  

  The variation is not reported in Uniprot.

• Click on the LOVD picture to check if a variant is described at position 1051    
  
  
  
  



• Graphical display of the region at NCBI (including SNPs)



• CYSMA Report:

  
  

  Report for p.Ile1051Phe variant

  CFTR orthologs conservation	The wild-type residue I1051 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs) The variant I1051F has never been found among the CFTR orthologs
  MSD2 homologs conservation	The wild-type residue I1051 belongs to the MSD2 domain and is conserved at 62.20% among the MSD2 homologs (79 / 127 MSD2 homologs) The variant I1051F has been found among the MSD2 homologs with a non significant frequency: 2.36% (3 / 127 MSD2 homologs)
  Structural effects	Solvent accessibility: the wild-type I1051 and the mutant I1051F are predicted to be buried The mutant residue is predicted to form comparable hydrophobic interactions than the wild-type The wild-type residue ILE is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is maintained in the mutant residue PHE The mutant residue might introduce steric clashes
  Allele frequency	The variant I1051V in gnomAD (123,136 exomes): 3.60e-05 ; variant I1051V in gnomAD (15,496 genomes): 3.23e-05 The variant I1051F in gnomAD (123,136 exomes): 4.00e-06
  Clinical significance	The variant I1051F has not been reported in ClinVar
  CFTR-France	The variant I1051F has not been described in CFTR-France
  Additional resources	SIFT prediction: variant I1051F is predicted to be damaging (score: 0.01) PPH2 prediction: variant I1051F is predicted to be damaging (score: 1)