PDBsum entry 4s0s

Immune system

PDB id: 4s0s

Contents

Protein chains

273 a.a.

90 a.a.

PDB id:

4s0s

Name:

Immune system

Title:

Structure of human pregnane x receptor ligand binding domain with adnectin-1

Structure:

Nuclear receptor subfamily 1 group i member 2. Chain: a, b. Synonym: orphan nuclear receptor par1, orphan nuclear receptor pxr, pregnane x receptor, steroid and xenobiotic receptor, sxr. Engineered: yes. Adnectin-1. Chain: d, e. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1i2, pxr. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.80Å R-factor: 0.217 R-free: 0.229

Authors:

J.A.Khan

Key ref:

J.A.Khan et al. (2015). Developing Adnectins that target SRC co-activator binding to PXR: a structural approach toward understanding promiscuity of PXR. J Mol Biol, 427, 924-942. PubMed id: 25579995 DOI: 10.1016/j.jmb.2014.12.022

Date:

05-Jan-15 Release date: 11-Feb-15

Protein chains

O75469  (NR1I2_HUMAN) -  Nuclear receptor subfamily 1 group I member 2 from Homo sapiens

Seq: 434 a.a.

Struc: 273 a.a.

Protein chains

No UniProt id for this chain

Struc: 90 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1016/j.jmb.2014.12.022

J Mol Biol 427:924-942 (2015)

PubMed id: 25579995

Developing Adnectins that target SRC co-activator binding to PXR: a structural approach toward understanding promiscuity of PXR.

J.A.Khan, D.M.Camac, S.Low, A.J.Tebben, D.L.Wensel, M.C.Wright, J.Su, V.Jenny, R.D.Gupta, M.Ruzanov, K.A.Russo, A.Bell, Y.An, J.W.Bryson, M.Gao, P.Gambhire, E.T.Baldwin, D.Gardner, C.L.Cavallaro, J.V.Duncia, J.Hynes.

ABSTRACT

The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain ((10)Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.