4O9S

Crystal structure of Retinol-Binding Protein 4 (RBP4)in complex with a non-retinoid ligand

Summary for 4O9S

• Entry DOI: 10.2210/pdb4o9s/pdb
• Related: 3FMZ 4PSQ
• Descriptor: Retinol-binding protein 4, 1-[4-(7-thia-9,11-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(12),2(6),8,10-tetraen-12-yl)piperazin-1-yl]-2-[2-(trifluoromethyl)phenyl]ethanone, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: retinol binding, disease mutation, retinol-binding, secreted, sensory transduction, transport, vision, vitamin a, transport protein, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 52636.94

Authors

Wang, Z.,Johnstone, S.,Walker, N.P. (deposition date: 2014-01-02, release date: 2014-07-02, Last modification date: 2024-10-16)

Primary citation

Wang, Y.,Connors, R.,Fan, P.,Wang, X.,Wang, Z.,Liu, J.,Kayser, F.,Medina, J.C.,Johnstone, S.,Xu, H.,Thibault, S.,Walker, N.,Conn, M.,Zhang, Y.,Liu, Q.,Grillo, M.P.,Motani, A.,Coward, P.,Wang, Z.
Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4.
Bioorg.Med.Chem.Lett., 24:2885-2891, 2014

PubMed Abstract: Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.

PubMed: 24835984
DOI: 10.1016/j.bmcl.2014.04.089

Experimental method

X-RAY DIFFRACTION (2.3 Å)