Difference between revisions of "Structure-based mutation analysis Gaucher Disease"

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[[File:mutations.png|thumb|left|400px|<caption>2nt0_A with the selected mutations of <xr id="tab:mutations"/>. Blue: wildtype residues; Red: mutant residues; Orange: active site residues E235 and E340.</caption>]]
  
[[File:mutations.png|thumb|left|400px|<caption>2nt0_A with the selected mutations of <xr id="tab:mutations"/>. Blue: wildtype residues; Red: mutant residues; Orange: active site residues E235 and E340.</caption>]]
 
</figure>
  
</figure>
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<br clear="all"/>
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== SCWRL ==
  +
<figure id="fig:scwrl">
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<gallery perrow=5 widths="100">
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File:scwrl_1.png|1: H60R
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File:scwrl_2.png|2: V172I
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File:scwrl_3.png|3: E111K
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File:scwrl_4.png|4: L197P
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File:scwrl_5.png|5: W209R
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File:scwrl_6.png|6: L470P
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File:scwrl_7.png|7: W312C
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File:scwrl_8.png|8: A384D
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File:scwrl_9.png|9: D443N
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File:scwrl_10.png|10: R44S
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</gallery>
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<caption>SNPs of <xr id="tab:mutations"/> introduced by SCWRL. Blue: wildtype residue; Red: mutant residue.</caption>
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</figure>
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<figtable id="tab:scwrl">
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{| style="border-collapse: separate; border-style: solid; border-spacing: 0; border-width: 2px 0 2px 0; text-align:center" width="700px"
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|- style="background-color: lightgrey"
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! rowspan="2" | Nr !! rowspan="2" style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Mutation !! colspan="2" style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Wildtype !! colspan="2" style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Mutatant !! rowspan="2"| Clashes !! rowspan="2" | Structural<br/>change
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|- style="background-color: lightgrey"
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! H-bonds !! style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobicity !! H-bonds !! style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobicity
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|-
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| colspan=8 style="border-collapse: separate; border-style: solid; border-spacing: 0; border-width: 1px 0 0 0"|
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|-
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| 1
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | H60R
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| T471 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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| G62 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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|| No || No
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|-
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| 2
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | V172I
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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|| No || No
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|-
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| 3
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | E111K
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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|| No || No
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|-
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| 4
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | L197P
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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|| No || No
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|-
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| 5
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | W209R
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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| T180 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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|| No || No
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|-
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| 6
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | L470P
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| T482 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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| T482 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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|| No || No
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|-
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| 7
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | W312C
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| E340, C342, P316 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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| E340, C342 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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|| No || No
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|-
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| 8
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | A384D
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophobic
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| V404 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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|| No || No
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|-
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| 9
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | D443N
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| || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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| V404 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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|| No || No
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|-
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| 10
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| style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | R44S
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| S13, Y487 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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| S13, Y487 || style="border-style: solid; border-spacing: 0; border-width: 0 1px 0 0;" | Hydrophilic
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| No || No
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|}
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<caption>Structure-based analysis of SNPs from <xr id="tab:mutations"/>. H-bonds: residues involved in forming hydrogen bonds (cut-off: 3.2 Å).</caption>
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</figtable>

Revision as of 17:20, 21 June 2012

Cystral structure

<figtable id="tab:mutations">

PDB Res [Å] R value Coverage pH
2nt0 1.80 0.18 96% (40-536) 4.5
3gxi 1.84 0.19 96% (40-536) 5.5
2v3f 1.95 0.15 96% (40-536) 6.5
2v3d 1.96 0.16 96% (40-536) 6.5
1ogs 2.00 0.18 96% (40-536) 4.6

The 5 crystral structures of glycosylceramidase with the highest resolution. The physiological lysosomal pH value is 4.5. 2nt0 was selected for the analysis. </figtable>

Mutations

<figtable id="tab:mutations">

Nr Pos
P04062		 Pos
2nt0_A		 From To Disease
causing
1 99 60 H R No
2 211 172 V I No
3 150 111 E K Yes
4 236 197 L P Yes
5 248 209 W R Yes
6 509 470 L P No
7 351 312 W C Yes
8 423 384 A D Yes
9 482 443 D N No
10 83 44 R S No

Mutations used for the structure-based mutation analysis. </figtable>

<figure id="fig:mutations">

2nt0_A with the selected mutations of <xr id="tab:mutations"/>. Blue: wildtype residues; Red: mutant residues; Orange: active site residues E235 and E340.

</figure>

SCWRL

<figure id="fig:scwrl">

  • 1: H60R

  • 2: V172I

  • 3: E111K

  • 4: L197P

  • 5: W209R

  • 6: L470P

  • 7: W312C

  • 8: A384D

  • 9: D443N

  • 10: R44S

SNPs of <xr id="tab:mutations"/> introduced by SCWRL. Blue: wildtype residue; Red: mutant residue. </figure>

<figtable id="tab:scwrl">

Nr Mutation Wildtype Mutatant Clashes Structural
change
H-bonds Hydrophobicity H-bonds Hydrophobicity
1 H60R T471 Hydrophilic G62 Hydrophilic No No
2 V172I Hydrophobic Hydrophobic No No
3 E111K Hydrophilic Hydrophilic No No
4 L197P Hydrophobic Hydrophobic No No
5 W209R Hydrophobic T180 Hydrophilic No No
6 L470P T482 Hydrophobic T482 Hydrophobic No No
7 W312C E340, C342, P316 Hydrophobic E340, C342 Hydrophilic No No
8 A384D Hydrophobic V404 Hydrophilic No No
9 D443N Hydrophilic V404 Hydrophilic No No
10 R44S S13, Y487 Hydrophilic S13, Y487 Hydrophilic No No

Structure-based analysis of SNPs from <xr id="tab:mutations"/>. H-bonds: residues involved in forming hydrogen bonds (cut-off: 3.2 Å). </figtable>

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