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Taming molecular flexibility to tackle rare diseases.

Cubellis MV, Baaden M, Andreotti G - Biochimie (2015)

Bottom Line: These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis.We found that mutations occurring at flexible sites are likely to retain activity in vivo.The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy. Electronic address: cubellis@unina.it.

No MeSH data available.


Related in: MedlinePlus

Crystal structure of AGAL (3GXT) in complex with DGJ (yellow). The structure was colored by RMSF ranging from blue (low flexibility) to white (medium flexibility) to red (high flexibility).
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fig1: Crystal structure of AGAL (3GXT) in complex with DGJ (yellow). The structure was colored by RMSF ranging from blue (low flexibility) to white (medium flexibility) to red (high flexibility).

Mentions: We carried out MD simulations using the structure of AGAL solved in the absence (3GXN) or in the presence (3GXT) of DGJ at pH 4.5 [30] as input. We run a 50 ns simulation at the same pH at which crystals were grown and calculated root mean square fluctuation (RMSF) values as a measure of flexibility per residue. In Fig. 1, the structure of AGAL solved in the presence of DGJ (3GXT) was colored by RMSF with colors ranging from blue (low flexibility) to white (medium flexibility) to red (high flexibility). AGAL is a homo-dimer and each subunit is made up by two domains, a TIM barrel where the active site is located and an antiparallel beta domain. Inspection of Fig. 1 suggests that flexibility is minimal in the regions not exposed to solvent buried between subunits, between domains or inside the TIM barrel.


Taming molecular flexibility to tackle rare diseases.

Cubellis MV, Baaden M, Andreotti G - Biochimie (2015)

Crystal structure of AGAL (3GXT) in complex with DGJ (yellow). The structure was colored by RMSF ranging from blue (low flexibility) to white (medium flexibility) to red (high flexibility).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4441037&req=5

fig1: Crystal structure of AGAL (3GXT) in complex with DGJ (yellow). The structure was colored by RMSF ranging from blue (low flexibility) to white (medium flexibility) to red (high flexibility).
Mentions: We carried out MD simulations using the structure of AGAL solved in the absence (3GXN) or in the presence (3GXT) of DGJ at pH 4.5 [30] as input. We run a 50 ns simulation at the same pH at which crystals were grown and calculated root mean square fluctuation (RMSF) values as a measure of flexibility per residue. In Fig. 1, the structure of AGAL solved in the presence of DGJ (3GXT) was colored by RMSF with colors ranging from blue (low flexibility) to white (medium flexibility) to red (high flexibility). AGAL is a homo-dimer and each subunit is made up by two domains, a TIM barrel where the active site is located and an antiparallel beta domain. Inspection of Fig. 1 suggests that flexibility is minimal in the regions not exposed to solvent buried between subunits, between domains or inside the TIM barrel.

Bottom Line: These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis.We found that mutations occurring at flexible sites are likely to retain activity in vivo.The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy. Electronic address: cubellis@unina.it.

No MeSH data available.


Related in: MedlinePlus