1DVX

CRYSTAL STRUCTURE OF HUMAN TRANSTHYRETIN IN COMPLEX WITH DICLOFENAC

Summary for 1DVX

• Entry DOI: 10.2210/pdb1dvx/pdb
• Related: 1BMZ 1DVQ 1DVS 1DVT 1DVU 1DVY 1DVZ
• Descriptor: TRANSTHYRETIN, 2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID (3 entities in total)
• Functional Keywords: thyroxine transport, signaling protein, hormone-growth factor complex, hormone/growth factor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27138.09

Authors

Klabunde, T.,Petrassi, H.M.,Oza, V.B.,Kelly, J.W.,Sacchettini, J.C. (deposition date: 2000-01-23, release date: 2001-01-23, Last modification date: 2024-12-25)

Primary citation

Klabunde, T.,Petrassi, H.M.,Oza, V.B.,Raman, P.,Kelly, J.W.,Sacchettini, J.C.
Rational design of potent human transthyretin amyloid disease inhibitors.
Nat.Struct.Biol., 7:312-321, 2000

PubMed 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.

PubMed: 10742177
DOI: 10.1038/74082

Experimental method

X-RAY DIFFRACTION (2 Å)