8DW5

Complex of Human Transthyretin with 3',5'-Dichlorophenylanthranilic Acid

Summary for 8DW5

• Entry DOI: 10.2210/pdb8dw5/pdb
• Descriptor: Transthyretin, 2-[(3,5-dichlorophenyl)amino]benzoic acid (3 entities in total)
• Functional Keywords: thyroid hormone distributor protein, amyloidogenic protein, protein transport
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15798.48

Authors

Truong, J.Q.,Holdsworth, B.,Holien, J.K. (deposition date: 2022-07-31, release date: 2022-08-10, Last modification date: 2023-10-25)

Primary citation

Cody, V.,Truong, J.Q.,Holdsworth, B.A.,Holien, J.K.,Richardson, S.J.,Chalmers, D.K.,Craik, D.J.
Structural Analysis of the Complex of Human Transthyretin with 3',5'-Dichlorophenylanthranilic Acid at 1.5 angstrom Resolution.
Molecules, 27:-, 2022

PubMed Abstract: Human transthyretin (hTTR) can form amyloid deposits that accumulate in nerves and organs, disrupting cellular function. Molecules such as tafamidis that bind to and stabilize the TTR tetramer can reduce such amyloid formation. Here, we studied the interaction of VCP-6 (2-((3,5-dichlorophenyl)amino)benzoic acid) with hTTR. VCP-6 binds to hTTR with 5 times the affinity of the cognate ligand, thyroxine (T). The structure of the hTTR:VCP-6 complex was determined by X-ray crystallography at 1.52 Å resolution. VCP-6 binds deeper in the binding channel than T with the 3',5'-dichlorophenyl ring binding in the 'forward' mode towards the channel centre. The dichlorophenyl ring lies along the 2-fold axis coincident with the channel centre, while the 2-carboxylatephenylamine ring of VCP-6 is symmetrically displaced from the 2-fold axis, allowing the 2-carboxylate group to form a tight intermolecular hydrogen bond with Nζ of Lys15 and an intramolecular hydrogen bond with the amine of VCP-6, stabilizing its conformation and explaining the greater affinity of VCP-6 compared to T. This arrangement maintains optimal halogen bonding interactions in the binding sites, via chlorine atoms rather than iodine of the thyroid hormone, thereby explaining why the dichloro substitution pattern is a stronger binder than either the diiodo or dibromo analogues.

PubMed: 36364032
DOI: 10.3390/molecules27217206

Experimental method

X-RAY DIFFRACTION (1.52 Å)