4psq

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

Structural highlights

4psq is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.4Å
Ligands:2WL, EDO, PO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RET4_HUMAN Defects in RBP4 are a cause of retinol-binding protein deficiency (RBP deficiency) [MIM:180250. This condition causes night vision problems. It produces a typical 'fundus xerophthalmicus', featuring a progressed atrophy of the retinal pigment epithelium.

Function

RET4_HUMAN Delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin, this prevents its loss by filtration through the kidney glomeruli.

Publication Abstract from PubMed

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.

Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4.,Wang Y, Connors R, Fan P, Wang X, Wang Z, Liu J, Kayser F, Medina JC, Johnstone S, Xu H, Thibault S, Walker N, Conn M, Zhang Y, Liu Q, Grillo MP, Motani A, Coward P, Wang Z Bioorg Med Chem Lett. 2014 Jul 1;24(13):2885-91. doi: 10.1016/j.bmcl.2014.04.089., Epub 2014 May 2. PMID:24835984[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Wang Y, Connors R, Fan P, Wang X, Wang Z, Liu J, Kayser F, Medina JC, Johnstone S, Xu H, Thibault S, Walker N, Conn M, Zhang Y, Liu Q, Grillo MP, Motani A, Coward P, Wang Z. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4. Bioorg Med Chem Lett. 2014 Jul 1;24(13):2885-91. doi: 10.1016/j.bmcl.2014.04.089., Epub 2014 May 2. PMID:24835984 doi:http://dx.doi.org/10.1016/j.bmcl.2014.04.089

Contents


PDB ID 4psq

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OCA

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