6z3i | pdb_00006z3i

Structure of recombinant beta-glucocerebrosidase in complex with bifunctional cyclophellitol aziridine activity based probe

spinqualitylabelsall models 6z3i, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6z3i is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: BMA, EDO, MAN, NAG, Q68, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GLCM_HUMAN Defects in GBA are the cause of Gaucher disease (GD) [MIM:230800; also known as glucocerebrosidase deficiency. GD is the most prevalent lysosomal storage disease, characterized by accumulation of glucosylceramide in the reticulo-endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset. [:] Defects in GBA are the cause of Gaucher disease type 1 (GD1) [MIM:230800; also known as adult non-neuronopathic Gaucher disease. GD1 is characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved.[:] Defects in GBA are the cause of Gaucher disease type 2 (GD2) [MIM:230900; also known as acute neuronopathic Gaucher disease. GD2 is the most severe form and is universally progressive and fatal. It manifests soon after birth, with death generally occurring before patients reach two years of age. Defects in GBA are the cause of Gaucher disease type 3 (GD3) [MIM:231000; also known as subacute neuronopathic Gaucher disease. GD3 has central nervous manifestations. Defects in GBA are the cause of Gaucher disease type 3C (GD3C) [MIM:231005; also known as pseudo-Gaucher disease or Gaucher-like disease. Defects in GBA are the cause of Gaucher disease perinatal lethal (GDPL) [MIM:608013. It is a distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism. Note=Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Defects in GBA contribute to susceptibility to Parkinson disease (PARK) [MIM:168600. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. Function GLCM_HUMAN Publication Abstract from PubMed Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in beta-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N-functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6- and N-functionalised reagents, a bi-functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes. Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents.,Rowland RJ, Chen Y, Breen I, Wu L, Offen WA, Beenakker TJ, Su Q, van den Nieuwendijk AMCH, Aerts JMFG, Artola M, Overkleeft HS, Davies GJ Chemistry. 2021 Sep 27. doi: 10.1002/chem.202102359. PMID:34570911 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acid-beta-glucosidase 3D structures

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