6MS7

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

Summary for 6MS7

• Entry DOI: 10.2210/pdb6ms7/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, PGC1 LXXLL motif, {[(1S)-1-(4-chlorophenyl)octyl]oxy}acetic acid, ... (4 entities in total)
• Functional Keywords: peroxisome proliferator-activated receptor gamma, lignad binding domain, selective ppar gamma modulator, vsp-77, dna binding protein, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 33030.42

Authors

Yi, W.,Jiang, H.,Zhou, X.E.,Shi, J.,Zhao, G.,Zhang, X.,Sun, Y.,Suino-Powell, K.,Li, J.,Li, J.,Melcher, K.,Xu, H.E. (deposition date: 2018-10-16, release date: 2019-10-23, Last modification date: 2024-03-13)

Primary citation

Jiang, H.,Zhou, X.E.,Shi, J.,Zhou, Z.,Zhao, G.,Zhang, X.,Sun, Y.,Suino-Powell, K.,Ma, L.,Gao, H.,Yu, X.,Li, J.,Li, J.,Melcher, K.,Xu, H.E.,Yi, W.
Identification and structural insight of an effective PPAR gamma modulator with improved therapeutic index for anti-diabetic drug discovery.
Chem Sci, 11:2260-2268, 2020

PubMed 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 and 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.

PubMed: 32190280
DOI: 10.1039/c9sc05487a

Experimental method

X-RAY DIFFRACTION (1.43 Å)