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Receptor Engineering

Rob Meijers, Ph.D.

About Receptor Engineering

We design and create protein tools to label, interrogate and manipulate cell surface receptors and their ligands.

Using state-of-the-art structural biology tools and mammalian expression protocols, our team produces human and mouse protein fragments that closely resemble their native state. We further engineer these fragments to probe the functional role of receptors. With our yeast display technology, we discover and produce synthetic antibodies that influence receptor conformation and ligand binding. These antibodies offer unprecedented insights into cell signaling and homeostasis and open new paths toward diagnostics and therapeutics to improve human health.

Research interests

The IPI Protein Design Group unites in silico and in vitro technologies to pursue three research interests.

The IPI Receptor Engineering Group uses high-throughput robotics, biophysical and molecular biology techniques to pursue three areas of research:

Axon guidance receptors

Cell surface receptors play an essential role in early brain development. They prod neurons to stretch and morph, thus, synapsing with other neurons. We have characterized the players in one critical receptor pathway: netrin. Highly conserved, netrin is a chemotrophic protein that concentrates and shapes into “paths” that attract or repulse the tips of axons as they sprout from neurons. Our work has uncovered the complex workings of several key netrin receptors. We are now developing synthetic antibodies for each to dissect their various responses to netrin’s selective clustering and patterning, triggering cell migration or apoptosis.

Wnt signaling

Wnt proteins create an essential molecular switch in homeostasis and proliferation, governing stem cell maintenance, axon guidance and tumor growth. The amino acid sequences of Wnt proteins and their receptors are evolutionarily conserved, creating challenges in discovering antibodies through traditional animal immunization. In response to the frustrating lack of antibodies in this crucial research area, we have initiated a campaign to discover synthetic antibodies that target all Wnt signaling pathway components. We deploy high-throughput protein production and yeast display technologies to discover and develop rare antibodies to this tough-to-target family of signaling molecules.

Opioid receptors

Opioid receptors are G protein-coupled receptors that mediate pain relief in injured and inflamed tissue. Sadly, the receptors also unleash adverse consequences in healthy tissue, including the slowdown of respiration and sedation of the brain. The side effects of opioids sit at the heart of a long-lasting and ever-growing opioid crisis worldwide. To address this problem, we obtained funding from the National Science Foundation to develop conformation-specific synthetic antibodies directed at opioid receptors. When a tissue becomes inflamed, opioid receptors respond by changing their conformation. Our goal is to create and wield antibodies that lock opioid receptors into specific states. These tools will allow us to probe opioid signaling mechanisms and speed the development of non-addictive narcotics.

READ MORE: The German Translation for Opioid

Expertise & Speciality

Receptor design and engineering

We are a team of scientists with expertise in the structural biology of cell surface receptors, especially those involved in immune responses, neuronal development and signaling. Some of our accomplishments include:

  • Engineering of major histocompatibility complex molecules to study peptide binding
  • Designing of fragments of the netrin guidance cue
  • Unraveling how netrin clusters cell surface receptors such as DCC, DSCAM and UNC5
  • Developing synthetic antibodies
  • Creating in vitro cell-based assays to label and manipulate proteins

High-throughput protein production and characterization

IPI is a perfect training ground for researchers who want to experience industrial-scale operations in an academic-like setting. We are equipped with state-of-the-art liquid handling robots and biophysical equipment to handle large numbers of protein constructs, protein expression screens and high-throughput biophysical characterization. Our equipment includes:

  • Beckman Coulter Biomek
  • Tecan
  • Dynamic devices
  • Lynx robots for liquid handling, transfection and purification
  • Miltenyi Automacs for sorting our yeast libraries
  • Becton Dickinson Melody FACS machines for yeast library sorting
  • maXis II Bruker QTOF mass spectrometer for biophysical characterization of our antigens and antibodies
  • HTX biolayer interferometer from Sartorius
  • Carterra LSA for surface plasmon resonance
  • State-of-the-art computational facilities on the Harvard campus

We also plan to deploy machine learning on the wealth of data obtained from our capabilities to better design and produce fit-for-purpose antibodies.

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