Summary for 5VZY
| Entry DOI | 10.2210/pdb5vzy/pdb |
| Related | 5VZX |
| Descriptor | Crenezumab Fab heavy chain,Immunoglobulin gamma-1 heavy chain, Crenezumab Fab light chain,Immunoblobulin light chain, Amyloid beta A4 protein, ... (4 entities in total) |
| Functional Keywords | immunoglobulin, immune system |
| Biological source | Homo sapiens More |
| Cellular location | Secreted : P0DOX5 Membrane; Single-pass type I membrane protein: P05067 |
| Total number of polymer chains | 3 |
| Total formula weight | 48820.30 |
| Authors | Ultsch, M.,Wang, W. (deposition date: 2017-05-29, release date: 2017-08-09, Last modification date: 2024-10-09) |
| Primary citation | Ultsch, M.,Li, B.,Maurer, T.,Mathieu, M.,Adolfsson, O.,Muhs, A.,Pfeifer, A.,Pihlgren, M.,Bainbridge, T.W.,Reichelt, M.,Ernst, J.A.,Eigenbrot, C.,Fuh, G.,Atwal, J.K.,Watts, R.J.,Wang, W. Structure of Crenezumab Complex with Abeta Shows Loss of beta-Hairpin. Sci Rep, 6:39374-, 2016 Cited by PubMed Abstract: Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of Aβ remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Aβ monoclonal IgG4 that binds multiple forms of Aβ, with higher affinity for aggregated forms, and that blocks Aβ 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 Aβ. 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 Aβ, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Aβ and breaks an essential salt-bridge characteristic of the β-hairpin conformation, eliminating features characteristic of the basic organization in Aβ 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 Aβ oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy. PubMed: 27996029DOI: 10.1038/srep39374 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.32 Å) |
Structure validation
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