4y9e | pdb_00004y9e

Crystal structure of V30M mutated transthyretin in complex with gamma-mangostin

spinqualitylabelsall models 4y9e, resolution 1.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4y9e 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: CL, MKT 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 homotetrameric protein involved in human hereditary amyloidoses. The discovery and development of small molecules that inhibit the amyloid fibril formation of TTR is one of the therapeutic strategies for these diseases. Herein, we discovered that gamma-mangostin (gamma-M) is an effective inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR. In-vitro binding assays revealed that gamma-M was the most potent of the selected xanthone derivatives, and it bound to the thyroxine (T4)-binding sites and stabilized the TTR tetramer. X-ray crystallographic analysis revealed the diagonal binding mode of gamma-M and the two binding sites of chloride ions at the T4-binding site. One of the chloride ions was replaced with a water molecule in the alpha-mangostin complex, which is a methylated derivative of gamma-M. The stronger inhibitory potency of gamma-M could be explained by the additional hydrogen bonds with the chloride ion. The present study establishes gamma-M as a novel inhibitor of TTR fibrillization. Discovery of gamma-Mangostin as an Amyloidogenesis Inhibitor.,Yokoyama T, Ueda M, Ando Y, Mizuguchi M Sci Rep. 2015 Aug 27;5:13570. doi: 10.1038/srep13570. PMID:26310724 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transthyretin 3D structures

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