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Insights into Hunter syndrome from the structure of iduronate-2-sulfatase

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Demydchuk, M 
Hill, CH 
Zhou, A 
Bunkóczi, G 
Stein, PE 


Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. A variety of disease-causing mutations have been identified throughout the IDS gene. However, understanding the molecular basis of the disease has been impaired by the lack of structural data. Here, we present the crystal structure of human IDS with a covalently bound sulfate ion in the active site. This structure provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. Understanding the structural consequences of disease-associated mutations will facilitate the identification of patients that may benefit from specific tailored therapies.



Catalytic Domain, Crystallography, X-Ray, Glycoproteins, Humans, Models, Molecular, Mucopolysaccharidosis II, Mutation, Protein Conformation, Protein Processing, Post-Translational, Sulfates

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Nature Communications

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Nature Publishing Group
Royal Society (UF150682)
Wellcome Trust (082961/Z/07/Z)
National Institutes of Health (NIH) (via University of California) (6801943)
Wellcome Trust (100140/Z/12/Z)
British Heart Foundation (None)
National Institute of General Medical Sciences (P01GM063210)
We acknowledge Diamond Light Source for time on beamline I03 under proposal MX6641. We thank Shire Pharmaceuticals for providing Elaprase (idursulfase) and Tom Terwilliger for helpful advice on multi-crystal averaging. We also thank Alexandre Bonvin for modifying HADDOCK to support the non-standard amino acid FGH (PDB code DDZ). R.J.R. is supported by a Principal Research Fellowship funded by the Wellcome Trust (Grant 082961/Z/07/Z), which also supported C.H.H. and M.D. A.Z. was supported by a Senior Research Fellowship from the British Heart Foundation (PG/09/072/27945). J.E.D. is supported by a Royal Society University Research Fellowship (UF100371). Support received from the US National Institutes of Health (grant P01GM063210 R.J.R.) is gratefully acknowledged. The research was facilitated by a Wellcome Trust Strategic Award (100140) to the Cambridge Institute for Medical Research.