8u52 | pdb_00008u52

Co-crystal structure of human transthyretin conjugated to the stilbene substructure derived from reaction with the fluorogenic covalent kinetic stabilizer A2

spinqualitylabelsall models 8u52, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u52 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 1.5Å Ligands: 1W4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TTHY_HUMAN Defects in TTR are the cause of amyloidosis transthyretin-related (AMYL-TTR) [MIM:105210. A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor. Defects in TTR are a cause of hyperthyroxinemia dystransthyretinemic euthyroidal (HTDE) [MIM:145680. It is a condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities. Defects in TTR are a cause of carpal tunnel syndrome type 1 (CTS1) [MIM:115430. It is a condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis. Function TTHY_HUMAN Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain. Publication Abstract from PubMed Transthyretin (TTR) is a natively tetrameric thyroxine transporter in blood and cerebrospinal fluid whose misfolding and aggregation causes TTR amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndamax) as a stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency approved for the treatment of TTR amyloidosis. Here we used cryo-EM to investigate the conformational landscape of this 55 kDa tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unobserved conformational states. These findings provide critical mechanistic insights into negatively cooperative ligand binding and the structural pathways responsible for TTR amyloidogenesis, underscoring the capacity of cryo-EM to identify pharmacological targets suppressed by the confines of the crystal lattice, opening uncharted territory in structure-based drug design. The conformational landscape of human transthyretin revealed by cryo-EM.,Basanta B, Nugroho K, Yan NL, Kline GM, Powers ET, Tsai FJ, Wu M, Hansel-Harris A, Chen JS, Forli S, Kelly JW, Lander GC Nat Struct Mol Biol. 2025 Jan 22. doi: 10.1038/s41594-024-01472-7. PMID:39843982 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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