ISSN:
1399-0047
Source:
Crystallography Journals Online : IUCR Backfile Archive 1948-2001
Topics:
Chemistry and Pharmacology
,
Geosciences
,
Physics
Notes:
The crystal structure of a new polymorphic form of human transthyretin (hTTR) with a lattice containing a unique assembly of apo hTTR and TTR–T4 complex has been determined to 3 Å resolution. The monoclinic form of human TTR reported here crystallizes in space group P21, with unit-cell parameters a = 76.7 (6), b = 96.7 (8), c = 81.7 (4) Å, β = 106.8 (4)°. The asymmetric unit contains two tetramers of transthyretin related by the non-crystallographic symmetry (NCS) operation of a 90.28° rotation between two hTTR molecules around an axis close to crystallographic z. The r.m.s. difference between the two tetramers calculated from their Cα positions is 0.48 Å. The structure was refined using 15.0–3.0 Å resolution data to R = 22.9% and Rfree = 28.9% for reflections F 〉 0.0σ(F), and R = 19.7% and Rfree = 25.8% for reflections F 〉 3.0σ(F). The intermolecular interactions involve the tips of α-helices and loops around Arg21, Glu61 and Ser100 of all monomers. The electron-density maps revealed residual thyroxine (T4) 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–T4 complex. The T4 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 β-strands of two monomeric subunits are observed between the apo TTR and T4-bound tetramer. The averaged distances between Ala108 Cα and its equivalent measured across each binding site are 12.34 Å for the T4-bound and 10.96 Å 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1107/S0907444901006047
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