1ict

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spinqualitylabelsall models 1ict, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

MONOCLINIC FORM OF HUMAN TRANSTHYRETIN COMPLEXED WITH THYROXINE (T4)

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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 A 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) A, 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 A. The, structure was refined using 15.0-3.0 A resolution data to R = 22.9% and, R(free) = 28.9% for reflections F > 0.0sigma(F), and R = 19.7% and R(free), = 25.8% for reflections F > 3.0sigma(F). The intermolecular interactions, involve the tips of alpha-helices and 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 averaged distances, between Ala108 C(alpha) and its equivalent measured across each binding, site are 12.34 A for the T(4)-bound and 10.96 A for the unliganded TTR, tetramer, respectively. The observed differences might reflect the, mechanics of the ligand binding in the channel and possibly explain the, observed negative cooperativity effect for ligand binding.

Disease

Known diseases associated with this structure: Amyloid neuropathy, familial, several allelic types OMIM:[176300], Amyloidosis, senile systemic OMIM:[176300], Carpal tunnel syndrome, familial OMIM:[176300], Dystransthyretinemic hyperthyroxinemia OMIM:[176300]

About this Structure

1ICT is a Single protein structure of sequence from Homo sapiens with T44 as ligand. Full crystallographic information is available from OCA.

Reference

Structure of a new polymorphic monoclinic form of human transthyretin at 3 A resolution reveals a mixed complex between unliganded and T4-bound tetramers of TTR., Wojtczak A, Neumann P, Cody V, Acta Crystallogr D Biol Crystallogr. 2001 Jul;57(Pt 7):957-67. Epub 2001, Jun 21. PMID:11418763

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