The Structural Biology Research Team at the RAS Initiative leads efforts to define the molecular architecture of RAS in complex with its effectors, regulators, and small molecules using NMR spectroscopy, X-ray crystallography, and cryo-electron microscopy. By elucidating these structures, the team seeks to uncover the mechanistic basis of RAS signaling and regulation. These insights not only deepen our understanding of RAS-driven biology but also enable the identification of novel targets and binding pockets for structure-guided drug discovery.

Structural insights into RAS biology and structure-based design

Our structure-function studies on oncogenic RAS mutants and RAS complexes with various effectors and regulators (GAPs and trafficking proteins) have provided significant structural and functional insights into RAS biology. 

Key accomplishments include:

  • RAS-PI3Kα Interaction Inhibitor: Development of BBO-10203, a small molecule that disrupts RAS-PI3Kα binding to inhibit tumor growth without inducing hyperglycemia.
  • Molecular Glues for Metabolic Modulation: Discovery of small molecules that enhance RAS-PI3Kα interaction to promote glucose uptake independently of insulin.
  • Structure-Guided Drug Design: Rational design of BBO-8520, a selective KRAS-G12C (GTP-bound) inhibitor.
  • RAS-PI3Kα Complex Structure: High-resolution structural analysis of the RAS-PI3Kα complex to define key interaction interfaces.
  • KRAS-RAF1 Complex Characterization: Structural elucidation of KRAS bound to RAF1's RBD-CRD domains.
  • KRAS Isoform Analysis: Comparative structural and biochemical studies of KRAS4A and KRAS4B isoforms.
  • RAF1 Chaperone Complex: Structural analysis of the RAF1-HSP90-CDC37 complex, revealing chaperone-assisted regulation of RAF1.
  • SHOC2-MRAS/KRAS-PP1C Complex: Elucidation of the architecture and assembly of the SHOC2 phosphatase complex with MRAS/KRAS and PP1C.
  • KRAS Mutant Dynamics: Investigation of the structural and conformational dynamics of oncogenic KRAS mutants.
  • RAS-SIN1 Interaction: Structural insights into the interaction between RAS and the SIN1 component of mTORC2.
  • KRAS-NF1 Complexes: Structural studies of KRAS bound to NF1 alone and in complex with SPRED1, informing regulation of RAS-GAP activity.
  • KRAS4B-PDEδ Interaction: Structural characterization of the KRAS4B-PDEδ complex, informing localization and trafficking mechanisms.
     

Our capabilities and specializations

The primary focus of our research is to utilize a combination of biochemical, structural and cell biological techniques to study the RAS signaling pathway and enable drug development through structure-based drug design, targeting RAS directly or indirectly.

The RAS Initiative Structural Biology Research Team is studying the structure of various oncogenic KRAS mutants and their complexes with different effectors and regulators to understand the structural, functional and mechanistic aspects of RAS biology.

A significant part of this team's effort also focuses on structure-guided hit/lead development in multiple ongoing drug discovery projects both internally and with CRADA partners.

Structural biology techniques

Elucidating dynamics and the three-dimensional structure of biomolecules at atomic resolution is critical for understanding vital biological processes, linking structure and function, and identifying new drug targets.

The RAS Initiative Structural Biology Research Team employs a range of structural biology techniques, including X-ray crystallography, cryo-electron microscopy (cryoEM), nuclear magnetic resonance (NMR), and various biophysical, biochemical, and cell biology assays. 

The team works closely with the Protein Expression Laboratory and is well equipped with crystallization robotics and an in-house X-ray generator, with regular access to the Titan Krios for cryoEM data collection and to the synchrotron beamlines at the Argonne and Brookhaven National Laboratories for crystallographic data collection.

Collaborators

The RAS Initiative Structural Biology Research Team collaborates with leading RAS researchers to gain new insights into the structure and function of RAS mutants and RAS complexes, including those with effectors and regulators. Our team is also engaged in multiple drug discovery projects with various biotech/pharma companies under the Cooperative Research and Development Agreements (CRADA) mechanism. 
 

Pharma/Biotech Collaborations

  • BridgeBio Oncology Therapeutics (BBOT)
  • Qubit Pharmaceuticals

Academic Collaborations

  • Pau Castel, Ph.D. – New York University Grossman School of Medicine
  • Andy Aguirre, M.D., Ph.D., and William Hahn, M.D., Ph.D. – Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard
  • Kevin Haigis, Ph.D. – Dana-Farber Cancer Institute, Harvard Medical School
  • Pablo Rodriguez-Viciana, Ph.D. – UCL Cancer Institute, University College London