6i6x | pdb_00006i6x

New Irreversible a-l-Iduronidase Inhibitors and Activity-Based Probes

spinqualitylabelsall models 6i6x, resolution 2.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6i6x is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, CL, GOL, H6B, MAN, NAG, TLA Related: 6i6r Activity: L-iduronidase, with EC number 3.2.1.76 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [IDUA_HUMAN] Hurler-Scheie syndrome;Hurler syndrome;Scheie syndrome. Defects in IDUA are the cause of mucopolysaccharidosis type 1H (MPS1H) [MIM:607014]; also known as Hurler syndrome. MPS1H is a severe form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1H usually present, within the first year of life, a combination of hepatosplenomegaly, skeletal deformities, corneal clouding and severe mental retardation. Obstructive airways disease, respiratory infection and cardiac complications usually result in death before 10 years of age. Defects in IDUA are the cause of mucopolysaccharidosis type 1H/S (MPS1H/S) [MIM:607015]; also known as Hurler-Scheie syndrome. MPS1H/S is a form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. MPS1H/S represents an intermediate phenotype of the MPS1 clinical spectrum. It is characterized by relatively little neurological involvement, but most of the somatic symptoms described for severe MPS1 develop in the early to mid-teens, causing considerable loss of mobility. Defects in IDUA are the cause of mucopolysaccharidosis type 1S (MPS1S) [MIM:607016]; also known as Scheie syndrome. MPS1S is a mild form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1S may have little or no neurological involvement, normal stature and life span, but present development of joints stiffness, mild hepatosplenomegaly, aortic valve disease and corneal clouding. Publication Abstract from PubMed Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity-based glycosidase probes (ABPs). Direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one-mediated aziridination of l-ido-configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of alpha-l-iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity-based manner with human recombinant alpha-l-iduronidase (rIDUA, Aldurazyme((R)) ). The structures of IDUA when complexed with the inhibitors in a non-covalent transition state mimicking form and a covalent enzyme-bound form provide insights into its conformational itinerary. Inhibitors 1-3 adopt a half-chair conformation in solution ((4) H3 and (3) H4 ), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1-3 may need to overcome an energy barrier in order to switch from the (4) H3 conformation to the transition state ((2, 5) B) binding conformation before reacting and adopting a covalent (5) S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients. New Irreversible alpha-l-Iduronidase Inhibitors and Activity-Based Probes.,Artola M, Kuo CL, McMahon SA, Oehler V, Hansen T, van der Lienden M, He X, van den Elst H, Florea BI, Kermode AR, van der Marel GA, Gloster TM, Codee JDC, Overkleeft HS, Aerts JMFG Chemistry. 2018 Oct 11. doi: 10.1002/chem.201804662. PMID:30307091 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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