Fabry:Structure-based mutation analysis

Fabry Disease » Structure-based mutation analysis

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The following analyses were performed on the basis of the α-Galactosidase A sequence. Please consult the journal for the commands used to generate the results.

Preparation

<figtable id="tab:Prep"> All available PDB structures assigned to the Uniprot entry P06280 along with the according Resolution,
Coverage and R-factor. The R-factor was obtained from the PDBsum page. The chosen structure 3S5Y is highlighted.

Entry	Method	Resolution (Å)	Chain	Positions (up to 429)	R-factor	R-free	pH	PDBsum	PDB
1R46	X-ray	3.25	A/B	32-422	0.262	0.301	8.0	[»]	[»]
1R47	X-ray	3.45	A/B	32-422	0.285	0.321	8.0	[»]	[»]
3GXN	X-ray	3.01	A/B	32-421	0.239	0.301	4.5	[»]	[»]
3GXP	X-ray	2.20	A/B	32-422	0.204	0.265	4.5	[»]	[»]
3GXT	X-ray	2.70	A/B	32-422	0.245	0.306	4.5	[»]	[»]
3HG2	X-ray	2.30	A/B	32-422	0.178	0.202	4.6	[»]	[»]
3HG3	X-ray	1.90	A/B	32-426	0.167	0.197	6.5	[»]	[»]
3HG4	X-ray	2.30	A/B	32-423	0.166	0.221	4.6	[»]	[»]
3HG5	X-ray	2.30	A/B	32-422	0.192	0.227	4.6	[»]	[»]
3LX9	X-ray	2.04	A/B	32-422	0.178	0.218	6.5	[»]	[»]
3LXA	X-ray	3.04	A/B	32-426	0.216	0.244	6.5	[»]	[»]
3LXB	X-ray	2.85	A/B	32-427	0.227	0.264	6.5	[»]	[»]
3LXC	X-ray	2.35	A/B	32-422	0.186	0.237	6.5	[»]	[»]
3S5Y	X-ray	2.10	A/B	32-422	0.195	0.230	5.1	[»]	[»]
3S5Z	X-ray	2.00	A/B	32-421	0.211	0.234	5.1	[»]	[»]
3TV8	X-ray	2.64	A/B	32-422	0.203	0.239	4.6	[»]	[»]

</figtable>

We did not choose to use the structure 3HG3, although it has the best resolution (1.90 Å) and the second best R-factor (see <xr id="tab:Prep"/>), which is a measure of the agreement between the crystallographic model and the experimental X-ray diffraction data <ref>R-factor (crystallography) (May 17, 2012‎) http://en.wikipedia.org/wiki/R-factor_%28crystallography%29, June 20, 2012</ref>, since it has an Alanin at position 170 (part of the active site) instead of an Aspartic acid. After excluding those structures, that had deviations in the sequence, we had to choose between ten sequences (1R46, 1R47, 3GXN, 3GXP, 3GXT, 3HG2, 3HG4, 3HG5, 3S5Y, 3S5Z) and decided to use 3S5Y. This structure has the advantage of a good pH, very good coverage and still reasonable resolution and R-factor.

Create mutation

SCWRL