4i87 | pdb_00004i87

Crystal structure of TTR variant I84S in complex with CHF5074 at acidic pH

spinqualitylabelsall models 4i87, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4i87 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: H50 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 Several classes of chemicals are able to bind to the thyroxine binding sites of transthyretin (TTR), stabilizing its native state and inhibiting in vitro the amyloidogenic process. The amyloidogenic I84S TTR variant undergoes a large conformational change at moderately acidic pH. Structural evidence has been obtained by X-ray analysis for the native state stabilization of I84S TTR by two chemically distinct fibrillogenesis inhibitors. In fact, they fully prevent the acidic pH-induced protein conformational change as a result of a long-range stabilizing effect. This study provides further support to the therapeutic strategy based on the use of TTR stabilizers as anti-amyloidogenic drugs. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: TTR and TTRbind by x-ray crystallography (View interaction). Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors.,Zanotti G, Cendron L, Folli C, Florio P, Imbimbo BP, Berni R FEBS Lett. 2013 Jun 20. pii: S0014-5793(13)00463-8. doi:, 10.1016/j.febslet.2013.06.016. PMID:23792159 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transthyretin 3D structures

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