4n86 | pdb_00004n86

Crystal structure of human transthyretin complexed with glabridin

spinqualitylabelsall models 4n86, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4n86 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, GBJ Related: 4n85, 4n87 Gene: TTR (HUMAN) 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 plasma protein implicated in human amyloid diseases. Several small molecules that bind to the thyroxine-binding site of TTR have been shown to stabilize the TTR tetramer and to inhibit amyloid fibril formation of TTR. Herein, we demonstrated that glabridin (Glab), a prenylated isoflavan isolated from Glycyrrhiza glabra L., inhibited aggregation of TTR in a thioflavin assay. The TTR-Glab complex structure revealed a novel binding mode including a CH-pi interaction with A108 and a hydrogen bond with K15. A structural comparison with the wild type-apo structure revealed that the CH-pi interaction with A108 was strengthened by the induced-fit conformational change upon Glab binding. Furthermore, the binding of Glab induced a rotation of the T119 side chain, and the inclusion of a water molecule, leading to stabilization of the dimer-dimer interface. These results demonstrate that Glab is a novel inhibitor of TTR fibrillization and suggest the molecular mechanism by which Glab binding stabilizes the tetramer. Crystal structures of human transthyretin complexed with glabridin.,Yokoyama T, Kosaka Y, Mizuguchi M J Med Chem. 2014 Feb 13;57(3):1090-6. doi: 10.1021/jm401832j. Epub 2014 Jan 23. PMID:24422526 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transthyretin

Proteopedia Page Contributors and Editors (what is this?)

OCA