FEB 27, 2019 7:30 AM PST

Keynote Presentation: Second Harmonic Generation Detection of Ras Conformational Changes and Discovery of a Novel Small-Molecule Binder

Presented at: Drug Discovery 2019
Speaker

Abstract

Second harmonic generation (SHG) is a biophysical method that sensitively measures real-time conformational change of biomolecules attached to membranes. SHG has recently been applied to detect protein conformational changes in the presence of biological ligands and small molecules. I will describe implementation of SHG as a primary screening platform to identify novel fragment ligands to oncogenic KRas. KRas is the most frequently mutated driver of pancreatic, colon, and lung cancers; however, there are few well-characterized small molecule ligands due to a lack of deep binding pockets. Using SHG, we identified a novel fragment binder to KRasG12D and then used 1H 15N HSQC NMR to characterize its binding site as a pocket adjacent to the Switch II region. The unique sensitivity of SHG furthered our study by revealing distinct conformations induced by our hit fragment compared to DCAI, a Ras ligand previously described to bind the same pocket, identified by fragment based NMR screening. This study highlights SHG as a high-throughput screening platform that reveals structural insights in addition to ligand binding.

Learning Objectives: 

1. Ras proteins, once considered “undruggable”, are now being subjected to a variety of new chemical and biophysical techniques to identify potential drugs that bins to shallow pockets in the protein
2. The biophysical phenomenon referred to as second harmonic generation (SHG) can be used as a tool for discovering molecules that bind to proteins of interest


Show Resources
You May Also Like
MAY 17, 2022 9:00 AM PDT
MAY 17, 2022 9:00 AM PDT
Date: May 17, 2022 Time: 9:00am (PDT), 12:00pm (EDT), 8:00pm (CEST) Gene therapeutics have great potential to treat many severe diseases in an unprecedented, targeted manner. The biopharmace...
MAR 16, 2022 8:00 AM PDT
C.E. CREDITS
MAR 16, 2022 8:00 AM PDT
Date: March 16, 2022 Time: 8:00am (PDT), 11:00am (EDT), 5:00pm (CET) Handling of potent and/or hazardous substances is commonplace in sev.....
APR 26, 2022 7:00 AM PDT
C.E. CREDITS
APR 26, 2022 7:00 AM PDT
Date: April 19, 2022 Time: 7:00am (PDT), 10:00am (EDT), 4:00pm (CEST) High-content (HC) phenotypic profiling approaches are a powerful tool to study the effect of biological, genetic, and ch...
SEP 13, 2022 8:00 AM PDT
SEP 13, 2022 8:00 AM PDT
Date: September 13, 2022 Time: 8:00am (PDT), 11:00am (EDT), 5:00pm (CEST) Preparedness against pandemic diseases demands rapid-response vaccine technology and ready-to-use analytical methods...
JUN 28, 2022 7:00 AM PDT
JUN 28, 2022 7:00 AM PDT
Date: June 28, 2022 Time: 3:00pm (BST), 4:00pm (CET), 9:00am (CST), 7am (PST) Light-sheet microscopy is an extremely versatile imaging technique with a vast range of implementations that are...
APR 28, 2022 8:00 AM PDT
APR 28, 2022 8:00 AM PDT
Date: April 28, 2022 Time: 8:00am (PDT), 11:00am (EDT), 5:00pm (CEST) Human pluripotent stem cells (PSCs) and their derivatives hold great potentials in...
FEB 27, 2019 7:30 AM PST

Keynote Presentation: Second Harmonic Generation Detection of Ras Conformational Changes and Discovery of a Novel Small-Molecule Binder

Presented at: Drug Discovery 2019


Show Resources
Loading Comments...
Show Resources
Attendees