PDBsum entry 3fmz

Transport protein

PDB id: 3fmz

Contents

Protein chains

174 a.a. *

Ligands

2T1 ×2

Waters ×11

* Residue conservation analysis

PDB id:

3fmz

Name:

Transport protein

Title:

Crystal structure of retinol-binding protein 4 (rbp4) in complex with non-retinoid ligand

Structure:

Retinol-binding protein 4. Chain: a, b. Synonym: plasma retinol-binding protein, prbp, rbp. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rbp4, pro2222. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.90Å R-factor: 0.226 R-free: 0.286

Authors:

Z.Wang,S.Johnstone,N.P.Walker

Key ref:

A.Motani et al. (2009). Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. J Biol Chem, 284, 7673-7680. PubMed id: 19147488 DOI: 10.1074/jbc.M809654200

Date:

22-Dec-08 Release date: 27-Jan-09

Protein chains

P02753  (RET4_HUMAN) -  Retinol-binding protein 4 from Homo sapiens

Seq: 201 a.a.

Struc: 174 a.a.

DOI no: 10.1074/jbc.M809654200

J Biol Chem 284:7673-7680 (2009)

PubMed id: 19147488

Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo.

A.Motani, Z.Wang, M.Conn, K.Siegler, Y.Zhang, Q.Liu, S.Johnstone, H.Xu, S.Thibault, Y.Wang, P.Fan, R.Connors, H.Le, G.Xu, N.Walker, B.Shan, P.Coward.

ABSTRACT

Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Analysis of the RBP4-A1120 co-crystal structure reveals that A1120 induces critical conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addition, we show that Rpb4(-/-) mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes.

Selected figure(s)

Figure 1.
In vitro characterization of A1120. A, chemical structure of A1120. B–D, representative radioligand binding isotherms for human RBP4 (B), mouse RBP4 (C), and human CRBP1 (D). In each case, [^3H]retinol was used as the radioligand. IC[50] values were 90 nm for hRBP4 (n = 11 independent determinations), 66 nm for mRBP4 (n = 4), and > 30 μm for hCRBP1 (n = 4). E, concentration-response curves in the FRET assay. Retinol was dosed in the presence of RBP4, TTR, and increasing concentrations of A1120 (0–1 × 10^-5 m, as shown on the right side). The K[i] of A1120 was 8.3 nm (n = 3).

Figure 2.
Co-crystal structure of human RBP4 with A1120. A, overall view of A1120-bound RBP4 structure. The RBP4 protein is shown in schematic representation with a spectrum color from blue (N terminus) to red (C terminus). A1120 is shown in stick representation with magenta for carbon atoms, red for oxygen atoms, blue for nitrogen atoms, and pale cyan for fluorine atoms. The 2f[o] - f[c] electron density map, contoured at 1σ, for A1120 is shown in gray mesh. B, protein-ligand interactions for A1120. The protein is shown in both stick (spectrum color) and molecular surface (wheat color) representations. The hydrogen bonds between RBP4 and A1120 are shown as black dashed lines. C, superposition of the A1120-RBP4 co-crystal structure and retinol-RBP4 co-crystal structure (PDB code: 1RBP). The carbon atoms are colored in gray for the retinol-bound structure. D, superposition of the A1120-RBP4 co-crystal structure on the RBP4·TTR complex structure (PDB code: 1QAB). The TTR tetramer is shown in molecule surface representation. The RBP4 proteins are shown in schematic representation with the RBP4 protein shown in gray in the TTR complex and in spectrum color in the A1120-bound form.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 7673-7680) copyright 2009.

Figures were selected by an automated process.