The atomic resolution structure of human aldose reductase reveals that rearrangement of a bound ligand allows the opening of the safety-belt loop

The crystal structure of human aldose reductase in complex with citrate has been determined to a resolution of 0.82 Å. The difference electron density for H atoms unequivocally shows that the cofactor is in the oxidized state corresponding to the situation after the catalytic event has occurred. A c...

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Bibliographic Details
Published in:Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2007-06, Vol.63 (6), p.665-672
Main Authors: Biadene, Marianna, Ginell, Steve, Cousido, Alexandra, Hazemann, Isabelle, Joachimiak, Andrzej, Sheldrick, George M., Podjarny, Alberto, Schneider, Thomas R.
Format: Article
Language:English
Subjects:
Aldehyde Reductase
Aldehyde Reductase - chemistry
Aldehyde Reductase - genetics
atomic resolution refinement
Biochemistry, Molecular Biology
Catalytic Domain
Citric Acid
Citric Acid - chemistry
Crystallography, X-Ray
diabetes mellitus
drug design
Electrostatics
Humans
Life Sciences
Ligands
Models, Molecular
Molecular biology
NADP(H)
Protein Conformation
Recombinant Proteins
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Static Electricity
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Summary:The crystal structure of human aldose reductase in complex with citrate has been determined to a resolution of 0.82 Å. The difference electron density for H atoms unequivocally shows that the cofactor is in the oxidized state corresponding to the situation after the catalytic event has occurred. A citrate molecule bound to the active site has been modelled in two different conformations. These two conformations correlate with a fully closed and a partially open conformation of the so‐called safety‐belt loop (Gly213–Ser226). The open conformation is observed for the first time with the cofactor bound to the protein and may be related to the initial phase of the opening of the safety belt. The structure suggests that after the catalytic event, a rearrangement of a bound ligand can trigger the opening of the safety‐belt loop, thus initiating the release of the oxidized cofactor.
ISSN:1399-0047
0907-4449
2059-7983
1399-0047
2059-7983
DOI:10.1107/S0907444907011997