Laura Heitman Group

Laura Heitman

Oncode Investigator at Leiden University (LACDR)

My Research

I focus on the theme “Novel receptor concepts to target membrane proteins” that has the potential for a large societal impact. I have selected membrane-bound proteins, such as G protein-coupled receptors (GPCRs), as many drugs act via these. I have been able to develop an array of novel in vitro equilibrium and kinetic binding assays, as well as (label-free) functional assays to investigate my research theme, with the ultimate aim to make medicines work better.

Within the field of GPCRs I am both nationally and internationally recognized as a leader, as shown by several top publications in this field (see ‘selected publications’ below). From the start of my career, i.e. as a PhD student, and by obtaining several competitive research grants (e.g. NWO-VENI, NWO-VIDI, IMI-K4DD), I have been able to independently build my own research line along two novel receptor concepts in particular, i.e. ‘Allosteric modulation of GPCRs’ and ‘Drug-target binding kinetics’. Together, these two concepts culminated in a 2016 Nature paper where we were able to identify a novel intracellular binding site for small molecule antagonists at the chemokine receptor CCR2. Interestingly, a consequence of both concepts is so-called insurmountable antagonism, i.e. antagonists that cannot be disrupted/counteracted by high local concentrations of the endogenous receptor agonist that is often causal to.

To this end, we combine and integrate different expertise and research domains relevant for modern future molecular pharmacology, such as receptor pharmacology, molecular and cellular biology, organic chemistry and computational chemistry. Here the implementation of future key technologies and methodologies is crucial, such as high throughput kinetic binding and signaling assays, both at cell membranes and on living cells. My team collaborates with crystallographers, cell biologists and in vivo pharmacologists, both from academia and pharmaceutical industry. Of note, medicinal chemistry research in academia typically has few, if any, links with the clinic, but the concepts that I work on have a large translational potential. Hence, I keep a keen eye on collaborating with research hospitals and pharmaceutical companies to go from an idea to proof-of-concept and continue to make my research translational in nature, next to being fundamental.

Awards

  • 2018: Oncode Junior Investigator (600 k€)
  • 2018: Prix Galien Research award 2018 (runner-up)
  • 2018: NWO-VIDI “Rethinking drug discovery – target binding kinetics as an essential paradigm” (800 k€)
  • 2018: Prize for a Young Medicinal Chemist in Academia by European Federation of Medicinal Chemistry (runner-up)
  • 2017: MedChemComm Emerging Investigator 2017 award by Royal Society of Chemistry
  • 2015: RPF “Establishment of structure-kinetics relationships to elucidate the mode of action of CB2 ligands” (233 k€)
  • 2013: IWT-O&O “Kinetic profiling as a novel concept for GPCR drug action” (294 k€)
  • 2012: Best lecturer at Leiden University by the Leiden Student Council (runner-up)
  • 2011: IMI "Kinetics for Drug Discovery" (1 M€)
  • 2010: NWO-VENI “Why do drugs fail in man? Drug-target residence time as a novel parameter in drug design and discovery” (250 k€)
  • 2009: “Discoverer of the Year 2009”-award from the Faculty of Science of Leiden University

Key Publications

  1. Zheng Y, Qin L, Zacarías NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH#, Tebben A, Kufareva I#, Handel TM#. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016, 540, 458 (#shared senior author)
  2. Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012, 337, 232-236
  3. Soethoudt M*, Grether U*, Fingerle J*, Grim TW, Fezza F, de Petrocellis L, Ullmer C, Rothenhausler B, Perret C, van Gils N, Finlay D, MacDonald C, Chicca A, Gens MD, Stuart J, de Vries H, Mastrangelo N, Xia L, Alachouzos G, Baggelaar M, Martella A, Mock ED, Deng H, Heitman LH#, Connor M#, di Marzo V#, Gertsch J#, Lichtman AH#, Maccarrone M#, Pacher P#, Glass M#, van der Stelt M#. Cannabinoid CB2 Receptor Ligand Profiling Reveals Biased Signaling and Off-target Activity: Implications for Drug Discovery. Nat Commun. 2017, 8, 13958 (#shared senior author)
  4. Bot I*, Ortiz Zacarías NV*, de Witte WE, de Vries H, van Santbrink PJ, van der Velden D, Kröner MJ, van der Berg DJ, Stamos D, de Lange EC, Kuiper J, IJzerman AP, Heitman LH. A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy. Sci. Rep. 2017, 7, 52
  5. Vlachodimou A, IJzerman AP, Heitman LH.Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1. Sci Rep. 2019, 9, 13802
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Laura Heitman Oncode Investigator

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