5vzx

Crystal structure of crenezumab Fab

spinqualitylabelsall models 5vzx, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5vzx is a 4 chain structure. This structure supersedes the now removed PDB entry 5kmv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EPE, MES, SO4 Related: 5vzy Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Accumulation of amyloid-beta (Abeta) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of Abeta remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Abeta monoclonal IgG4 that binds multiple forms of Abeta, with higher affinity for aggregated forms, and that blocks Abeta aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with Abeta. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab's versatile binding profile. We find interactions consistent with high affinity for multiple forms of Abeta, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Abeta and breaks an essential salt-bridge characteristic of the beta-hairpin conformation, eliminating features characteristic of the basic organization in Abeta oligomers and fibrils, and explains crenezumab's inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumab's unique mechanism of action, particularly regarding Abeta oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy. Structure of Crenezumab Complex with Abeta Shows Loss of beta-Hairpin.,Ultsch M, Li B, Maurer T, Mathieu M, Adolfsson O, Muhs A, Pfeifer A, Pihlgren M, Bainbridge TW, Reichelt M, Ernst JA, Eigenbrot C, Fuh G, Atwal JK, Watts RJ, Wang W Sci Rep. 2016 Dec 20;6:39374. doi: 10.1038/srep39374. PMID:27996029 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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