Difference between revisions of "Task 9 (MSUD)"

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m (→‎Visualization of mutant structures)
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<tr><td>dbSNP</td><td>rs61736656</td><td>I361V </td><td>False</td></tr>
  
<tr><td>dbSNP</td><td>rs61736656</td><td>I361V </td><td>False</td></tr>
 
</table>
  
</table>
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  +
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===Selection of structure model===
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  +
The following table shows an overview of all structures that are available for our protein:
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  +
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{| class='wikitable' border='1' style='width:800px'
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! Entry !! Method !! Resolution [Å] !! Chain !! Positions !! R-value !! pH !! gaps
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|-
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| 2BFD || X-ray || 1.39 || A || 46-445 || 0.15 || 5.5 || 289GLY-292SER,293THR-313ASP
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|- style="background-color: #FFBBBB;"
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| 2BFF || X-ray || 1.46 || A || 46-445 || 0.15 || 5.5 || 301ARG-305GLU
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|-
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| 1X7Y || X-ray || 1.57 || A || 46-445 || 0.15 || 5.8 || 287ARG-313ASP
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|-
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| 2BFC || X-ray || 1.64 || A || 46-445 || 0.144 || 5.5 || 288ILE-313ASP
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|-
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| 2BFE || X-ray || 1.69 || A || 46-445 || 0.15 || 5.5 || 289GLY-291HIS,293THR-313ASP
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|-
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| 1X7Z || X-ray || 1.72 || A || 46-445 || 0.154 || 5.8 || 301ARG-306VAL
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|-
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| 1X7W || X-ray || 1.73 || A || 46-445 || 0.148 || 5.8 || 287ARG-313ASP
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|-
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| 2BFB || X-ray || 1.77 || A || 46-445 || 0.145 || 5.5 || 287ARG-313ASP
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|-
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| 2BEW || X-ray || 1.79 || A || 46-445 || 0.147 || 5.5 || 301ARG-307ASN
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|-
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| 1V1R || X-ray || 1.8 || A || 46-445 || 0.158 || 5.5 || 222ASN-231SER,286TYR-314HIS
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|-
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| 2BEV || X-ray || 1.8 || A || 46-445 || 0.139 || 5.5 || 301ARG-307ASN
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|-
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| 1U5B || X-ray || 1.83 || A || 46-445 || 0.156 || 5.8 || 301ARG-306VAL
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|-
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| 1WCI || X-ray || 1.84 || A || 46-445 || 0.149 || 5.5 || 301ARG-309TRP
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|-
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| 1OLS || X-ray || 1.85 || A || 46-445 || 0.172 || 5.5 || 292SER-295ASP,298SER-300TYR,301ARG-308TYR
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|-
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| 2J9F || X-ray || 1.88 || A/C || 46-445 || 0.171 || 5.5 || 300TYR-313ASP
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|-
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| 2BEU || X-ray || 1.89 || A || 46-445 || 0.171 || 5.5 || 301ARG-307ASN
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|-
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| 1OLU || X-ray || 1.9 || A || 46-445 || 0.161 || 5.5 || 26ASN-30GLY,287ARG-313ASP
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|-
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| 1V16 || X-ray || 1.9 || A || 46-445 || 0.132 || 5.5 || 288ILE-313ASP
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|-
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| 1V11 || X-ray || 1.95 || A || 46-445 || 0.139 || 5.5 || 288ILE-313ASP
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|-
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| 1V1M || X-ray || 2 || A || 46-445 || 0.13 || 5.5 || 289GLY-313ASP
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|-
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| 1X80 || X-ray || 2 || A || 46-445 || 0.161 || 5.8 || 287ARG-313ASP
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|-
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| 1X7X || X-ray || 2.1 || A || 46-445 || 0.149 || 5.8 || 287ARG-313ASP
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|-
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| 1OLX || X-ray || 2.25 || A || 46-445 || 0.161 || 5.5 || 301ARG-307ASN
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|-
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| 1DTW || X-ray || 2.7 || A || 46-445 || 0.224 || 7.5 || 301ARG-314HIS
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|}
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Unfortunately all structures contain gaps that span positions 302-304 (corresponding to 347-349 in the reference sequence), so we cannot create a composite structure, that does not contain this gap. We chose 2BFF because it has the smallest gap, a good resolution and a low R-value. It is not resolved at physiological pH, but the only structure with pH 7.5 (1DTW) has a bad resolution. The RMSD between 2BFF and 1DTW is about 0.3, so the different pH does not lead to a different structure and therefore the low pH at that 2BFF was resolved should not be a problem.
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===Visualization of mutant structures===
  
===Visualization of mutant structures===

Revision as of 16:47, 12 July 2013

Results

Lab journal

For this task we have chosen 5 mutations from HGMD and dbSNP. 2 of them are neutral mutations which do not have functional changes over the protein structure. Following are the 5 mutations:

DatabaseAccession_codeMutationPathogenic
dbSNPrs11549938M82LFalse
dbSNPrs141086188A222TFalse
HGMDCM045934C264WTrue
HGMDCM062448R346HTrue
dbSNPrs61736656I361V False


Selection of structure model

The following table shows an overview of all structures that are available for our protein:


Entry Method Resolution [Å] Chain Positions R-value pH gaps
2BFD X-ray 1.39 A 46-445 0.15 5.5 289GLY-292SER,293THR-313ASP
2BFF X-ray 1.46 A 46-445 0.15 5.5 301ARG-305GLU
1X7Y X-ray 1.57 A 46-445 0.15 5.8 287ARG-313ASP
2BFC X-ray 1.64 A 46-445 0.144 5.5 288ILE-313ASP
2BFE X-ray 1.69 A 46-445 0.15 5.5 289GLY-291HIS,293THR-313ASP
1X7Z X-ray 1.72 A 46-445 0.154 5.8 301ARG-306VAL
1X7W X-ray 1.73 A 46-445 0.148 5.8 287ARG-313ASP
2BFB X-ray 1.77 A 46-445 0.145 5.5 287ARG-313ASP
2BEW X-ray 1.79 A 46-445 0.147 5.5 301ARG-307ASN
1V1R X-ray 1.8 A 46-445 0.158 5.5 222ASN-231SER,286TYR-314HIS
2BEV X-ray 1.8 A 46-445 0.139 5.5 301ARG-307ASN
1U5B X-ray 1.83 A 46-445 0.156 5.8 301ARG-306VAL
1WCI X-ray 1.84 A 46-445 0.149 5.5 301ARG-309TRP
1OLS X-ray 1.85 A 46-445 0.172 5.5 292SER-295ASP,298SER-300TYR,301ARG-308TYR
2J9F X-ray 1.88 A/C 46-445 0.171 5.5 300TYR-313ASP
2BEU X-ray 1.89 A 46-445 0.171 5.5 301ARG-307ASN
1OLU X-ray 1.9 A 46-445 0.161 5.5 26ASN-30GLY,287ARG-313ASP
1V16 X-ray 1.9 A 46-445 0.132 5.5 288ILE-313ASP
1V11 X-ray 1.95 A 46-445 0.139 5.5 288ILE-313ASP
1V1M X-ray 2 A 46-445 0.13 5.5 289GLY-313ASP
1X80 X-ray 2 A 46-445 0.161 5.8 287ARG-313ASP
1X7X X-ray 2.1 A 46-445 0.149 5.8 287ARG-313ASP
1OLX X-ray 2.25 A 46-445 0.161 5.5 301ARG-307ASN
1DTW X-ray 2.7 A 46-445 0.224 7.5 301ARG-314HIS


Unfortunately all structures contain gaps that span positions 302-304 (corresponding to 347-349 in the reference sequence), so we cannot create a composite structure, that does not contain this gap. We chose 2BFF because it has the smallest gap, a good resolution and a low R-value. It is not resolved at physiological pH, but the only structure with pH 7.5 (1DTW) has a bad resolution. The RMSD between 2BFF and 1DTW is about 0.3, so the different pH does not lead to a different structure and therefore the low pH at that 2BFF was resolved should not be a problem.


Visualization of mutant structures

The mutagen tool of PyMOL was used to introduce mutations to the protein structure. Mutations and their neighboring residues are visualized and shown in following figures.

  • Visualization of mutations in BCKDHA (PDB: 2BFF, all residue positions refer to the reference sequence of BCKDHA)

  • Local environment of residue 82. Original methionine is replaced by leucine.

  • Local environment of residue 222. Original alanine is replaced by threonine.

  • Local environment of residue 264. Original cysteine is replaced by tryptophan. Clearly, the mutant residue tryptophan clashes with the binding site (Green) for ion binding.

  • Local environment of residue 346. Original arginine is replaced by histidine.

  • Local environment of residue 361. Original isoleucine is replaced by valine.

Mutant structures (SCWRL)

Energy comparisons

FoldX

Minimise

Gromacs

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