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Titolo:
Structure of a new polymorphic monoclinic form of human transthyretin at 3angstrom resolution reveals a mixed complex between unliganded and T-4-bound tetramers of TTR
Autore:
Wojtczak, A; Neumann, P; Cody, V;
Indirizzi:
Hauptman Woodward Med Res Inst Inc, Buffalo, NY 14203 USA Hauptman Woodward Med Res Inst Inc Buffalo NY USA 14203 alo, NY 14203 USA Nicholas Copernicus Univ, Inst Chem, PL-87100 Torun, Poland Nicholas Copernicus Univ Torun Poland PL-87100 m, PL-87100 Torun, Poland
Titolo Testata:
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
, volume: 57, anno: 2001,
parte:, 7
pagine: 957 - 967
SICI:
0907-4449(200107)57:<957:SOANPM>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID FIBRIL FORMATION; CRYSTAL-STRUCTURE DETERMINATION; VAPOR-DIFFUSION TECHNIQUE; HUMAN SERUM TRANSTHYRETIN; ELECTRON-DENSITY MAPS; PROTEIN MODELS; BINDING; VARIANT; DISEASE; PREALBUMIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Cody, V Hauptman Woodward Med Res Inst Inc, 73 High St, Buffalo, NY 14203 USA Hauptman Woodward Med Res Inst Inc 73 High St Buffalo NY USA 14203
Citazione:
A. Wojtczak et al., "Structure of a new polymorphic monoclinic form of human transthyretin at 3angstrom resolution reveals a mixed complex between unliganded and T-4-bound tetramers of TTR", ACT CRYST D, 57, 2001, pp. 957-967

Abstract

The crystal structure of a new polymorphic form of human transthyretin (hTTR) with a lattice containing a unique assembly of apo hTTR and TTR-T-4 complex has been determined to 3 Angstrom resolution. The monoclinic form of human TTR reported here crystallizes in space group P2(1), with unit-cell parameters a = 76.7 (6), b = 96.7 (8), c = 81.7 (4) Angstrom, beta = 106.8 (4)degrees. The asymmetric unit contains two tetramers of transthyretin related by the non-crystallographic symmetry (NCS) operation of a 90.28 degrees rotation between two hTTR molecules around an axis close to crystallographic z. The r.m.s. difference between the two tetramers calculated from their C-alpha positions is 0.48 Angstrom. The structure was refined using 15.0-3.0 Angstrom resolution data to R = 22.9% and R-free = 28.9% for reflections F>0.0 sigma (F), and R = 19.7% and R-free = 25.8% for reflections F >3.0 sigma (F). The intermolecular interactions involve the tips of alpha -helicesand loops around Arg21, Glu61 and Ser100 of all monomers. The electron-density maps revealed residual thyroxine (T-4) bound in only one of the two unique tetrameric TTR molecules, with an occupancy of 53%, while the second tetramer is unliganded. One thyroxine ligand is bound in a way similar to the orientations described for the orthorhombic form of the hTTR-T-4 complex. The T-4 bound in the second site is positioned similar to 3',5'-dinitro-N-acetyl-L-thyronine in its hTTR complex. Differences in the size of the central channel defined by the D, A, G and H beta -strands of two monomeric subunits are observed between the apo TTR and T-4-bound tetramer. The averageddistances between Ala108 C-alpha and its equivalent measured across each binding site are 12.34 Angstrom for the T-4-bound and 10.96 Angstrom for theunliganded TTR tetramer, respectively. The observed differences might reflect the mechanics of the ligand binding in the channel and possibly explainthe observed negative cooperativity effect for ligand binding.

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Documento generato il 01/04/20 alle ore 10:02:59