4tqi | pdb_00004tqi

Human transthyretin (TTR) complexed with 3-(9H-fluoren-9-ylideneaminooxy)propanoic acid in a dual binding mode

spinqualitylabelsall models 4tqi, resolution 1.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4tqi 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. Ligands: 6BD, GOL 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 54 kDa homotetrameric protein that transports thyroxine (T4) and retinol (vitamin A), through its association with retinol binding protein (RBP). Under unknown conditions, it aggregates to form fibrils associated with TTR amyloidosis. Ligands able to inhibit fibril formation have been studied by X-ray crystallography. The use of polyethylene glycol (PEG) instead of ammonium sulphate or citrate has been evaluated as an alternative to obtain new TTR complexes with (R)-3-(9-fluoren-9-ylideneaminooxy)-2-methyl-N-(methylsulfonyl) propionamide (48R(1)) and 2-(9H-fluoren-9-ylideneaminooxy) acetic acid (ES8(2)). The previously described fluorenyl based inhibitors (S)-3-((9H-fluoren-9-ylideneamino)oxy)-2-methylpropanoic acid (6BD) and 3-((9H-fluoren-9-ylideneamino)oxy)propanoic acid (7BD) have been re-evaluated with the changed crystallization method. The new TTR complexes with compounds of the same family show that the 9-fluorenyl motif can occupy alternative hydrophobic binding sites. This augments the potential use of this scaffold to yield a large variety of differently substituted mono-aryl compounds able to inhibit TTR fibril formation. X-ray crystal structure and activity of fluorenyl-based compounds as transthyretin fibrillogenesis inhibitors.,Ciccone L, Nencetti S, Rossello A, Tepshi L, Stura EA, Orlandini E J Enzyme Inhib Med Chem. 2015 Aug 3:1-10. PMID:26235916 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transthyretin 3D structures

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