PDBsum entry 1dvq

Hormone/growth factor

PDB id: 1dvq

Contents

Protein chain

115 a.a. *

Waters ×59

* Residue conservation analysis

PDB id:

1dvq

Name:

Hormone/growth factor

Title:

Crystal structure of human transthyretin

Structure:

Transthyretin. Chain: a, b. Synonym: prealbumin. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.00Å R-factor: 0.203 R-free: 0.223

Authors:

T.Klabunde,H.M.Petrassi,V.B.Oza,J.W.Kelly,J.C.Sacchettini

Key ref:

T.Klabunde et al. (2000). Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol, 7, 312-321. PubMed id: 10742177 DOI: 10.1038/74082

Date:

22-Jan-00 Release date: 22-Jan-01

Protein chains

P02766  (TTHY_HUMAN) -  Transthyretin from Homo sapiens

Seq: 147 a.a.

Struc: 115 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1038/74082

Nat Struct Biol 7:312-321 (2000)

PubMed id: 10742177

Rational design of potent human transthyretin amyloid disease inhibitors.

T.Klabunde, H.M.Petrassi, V.B.Oza, P.Raman, J.W.Kelly, J.C.Sacchettini.

ABSTRACT

The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.

Selected figure(s)

Figure 5.
Figure 5. Comparison of binding of flurbiprofen to TTR and COX-2. a, Hormone binding channel of TTR with bound flurbiprofen. In each binding conformation flurbiprofen fills three halogen binding pockets: the phenyl ring binds into the innermost HBP-3, the fluorine substituent into HBP-2, and the -methyl group into HBP-1. b, Binding of the anti-inflammatory flurbiprofen into the prostaglandin binding channel of COX-2 (PDB 3PGH)28. The binding channel has two entrances, one on the top and one on the left. The CH[2]COOH group of flurbiprofen is positioned at one of the entries close to the gate residue Arg 120 and thus allows the formation of a salt bridge. As in the TTR -FLP complex further protein -ligand interactions are augmented by hydrophobic interactions between the biphenyl moiety of the drug and hydrophobic protein residues.

Figure 6.
Figure 6. Hormone binding channel of TTR with bound novel designed amyloid inhibitors. a, o-trifluoromethylphenyl anthranilic acid (oFLU). b, Dibenzofuran-4,6-dicarboxylic acid (DDBF), c, N-m-trifluoromethylphenyl-phenoxazine-4,6-dicarboxylic acid (PHENOX).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 312-321) copyright 2000.

Figures were selected by an automated process.