5kk7

Crystal structure of the class I human endoplasmic reticulum 1,2-alpha-mannosidase T688A mutant and Thio-disaccharide substrate analog complex

spinqualitylabelsall models 5kk7, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5kk7 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. Method: X-ray diffraction, Resolution 1.7324Å Ligands: 1PS, ACT, BU1, CA, MAN, PRD_900033, SO4, Z5L Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MA1B1_HUMAN Defects in MAN1B1 are the cause of mental retardation autosomal recessive type 15 (MRT15) [MIM:614202. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Function MA1B1_HUMAN Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man(9)GlcNAc(2) to produce Man(8)GlcNAc(2), but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man(5-6)GlcNAc(2). Publication Abstract from PubMed Maturation of Asn-linked oligosaccharides in the eukaryotic secretory pathway requires the trimming of nascent glycan chains to remove all glucose and several mannose residues before extension into complex-type structures on the cell surface and secreted glycoproteins. Multiple glycoside hydrolase family 47 (GH47) alpha-mannosidases, including endoplasmic reticulum (ER) alpha-mannosidase I (ERManI) and Golgi alpha-mannosidase IA (GMIA), are responsible for cleavage of terminal alpha1,2-linked mannose residues to produce uniquely trimmed oligomannose isomers that are necessary for ER glycoprotein quality control and glycan maturation. ERManI and GMIA have similar catalytic domain structures, but each enzyme cleaves distinct residues from tribranched oligomannose glycan substrates. The structural basis for branch-specific cleavage by ERManI and GMIA was explored by replacing an essential enzyme-bound Ca2+ ion with a lanthanum (La3+) ion. This ion swap led to enzyme inactivation while retaining high-affinity substrate interactions. Cocrystallization of La3+-bound enzymes with Man9GlcNAc2 substrate analogs revealed enzyme-substrate complexes with distinct modes of glycan branch insertion into the respective enzyme active-site clefts. Both enzymes had glycan interactions that extended across the entire glycan structure, but each enzyme engaged a different glycan branch and used different sets of glycan interactions. Additional mutagenesis and time-course studies of glycan cleavage probed the structural basis of enzyme specificity. The results provide insights into the enzyme catalytic mechanisms and reveal structural snapshots of the sequential glycan cleavage events. The data also indicate that full steric access to glycan substrates determines the efficiency of mannose-trimming reactions that control the conversion to complex-type structures in mammalian cells. Substrate recognition and catalysis by GH47 alpha-mannosidases involved in Asn-linked glycan maturation in the mammalian secretory pathway.,Xiang Y, Karaveg K, Moremen KW Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):E7890-E7899. Epub 2016 Nov 17. PMID:27856750 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Mannosidase 3D structures

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