X-ray structure of PTP1B in complex with a new PTP1B inhibitor
M V V V Sekhar Reddy, Chakshumathi Ghadiyaram, Sunil Kumar Panigrahi
1Aurigene Discovery Technologies Ltd, 39-40 KIADB Industrial Area, Phase II, Electronic city, Hosur Road, Bangalore-560100, India. manusekhar1975@gmail.com.
Abstract:
Protein tyrosine phosphatase 1B (PTP1B) is a prototype non receptor cytoplasmic PTPase enzyme that has been implicated in regulation of insulin and leptin signaling pathways. Studies on PTP1B knockout mice and PTP1B antisense treated mice suggested that inhibition of PTP1B would be an effective strategy for the treatment of type II diabetes and obesity. Here we report the X-ray structure of PTP1B in complex with compound IN1834-146C (PDB ID 4I8N). The crystals belong to P3121 space group with cell dimensions (a = b = 87.89 Å, c = 103.68 Å) diffracted to 2.5 Å. The crystal structure contained one molecule of protein in the asymmetric unit and was solved by molecular replacement method. The compound engages both catalytic site and allosteric sites of PTP1B protein. We described the molecular interaction of the compound with the active site residues of PTP1B in this crystal structure report.
Insights
This study reports the X-ray structure of protein tyrosine phosphatase 1B (PTP1B) complexed with IN1834-146C. The findings offer insights into PTP1B inhibition for treating type II diabetes and obesity.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of insulin and leptin signaling pathways.
- Inhibiting PTP1B is a promising therapeutic strategy for type II diabetes and obesity.
Purpose of the Study:
- To determine the X-ray crystal structure of PTP1B in complex with the inhibitor IN1834-146C.
- To elucidate the molecular interactions between IN1834-146C and PTP1B at both catalytic and allosteric sites.
Main Methods:
- X-ray crystallography
- Molecular replacement method
- Analysis of protein-ligand interactions
Main Results:
- The crystal structure of PTP1B complexed with IN1834-146C was determined at 2.5 Å resolution (PDB ID 4I8N).
- The inhibitor IN1834-146C binds to both the catalytic and allosteric sites of PTP1B.
- Detailed molecular interactions with active site residues were described.
Conclusions:
- The elucidated structure provides a molecular basis for PTP1B inhibition by IN1834-146C.
- This structural information can guide the development of novel PTP1B inhibitors for metabolic diseases.
