PDBsum entry 6ms7

Transcription

PDB id: 6ms7

Contents

Protein chains

265 a.a.

11 a.a.

Ligands

V77 ×2

Waters ×272

PDB id:

6ms7

Name:

Transcription

Title:

Peroxisome proliferator-activated receptor gamma ligand binding domain in complex with a novel selective ppar-gamma modulator vsp-77

Structure:

Peroxisome proliferator-activated receptor gamma. Chain: a. Synonym: ppar-gamma,nuclear receptor subfamily 1 group c member 3. Engineered: yes. Pgc1 lxxll motif. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pparg, nr1c3. Expressed in: escherichia coli 042. Expression_system_taxid: 216592. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

1.43Å R-factor: 0.187 R-free: 0.208

Authors:

W.Yi,H.Jiang,X.E.Zhou,J.Shi,G.Zhao,X.Zhang,Y.Sun,K.Suino-Powell,J.Li, J.Li,K.Melcher,H.E.Xu

Key ref:

H.Jiang et al. (2020). Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery. Chem Sci, 11, 2260-2268. PubMed id: 32190280 DOI: 10.1039/c9sc05487a

Date:

16-Oct-18 Release date: 23-Oct-19

Protein chain

P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma from Homo sapiens

Seq: 505 a.a.

Struc: 265 a.a.*

Protein chain

Q9UBK2  (PRGC1_HUMAN) -  Peroxisome proliferator-activated receptor gamma coactivator 1-alpha from Homo sapiens

Seq: 798 a.a.

Struc: 11 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1039/c9sc05487a

Chem Sci 11:2260-2268 (2020)

PubMed id: 32190280

Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery.

H.Jiang, X.E.Zhou, J.Shi, Z.Zhou, G.Zhao, X.Zhang, Y.Sun, K.Suino-Powell, L.Ma, H.Gao, X.Yu, J.Li, J.Li, K.Melcher, H.E.Xu, W.Yi.

ABSTRACT

Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARγ-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARγ modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs.