Dynaflow Resolve Science

Selected publications

Rational antibody design for undruggable targets using kinetically controlled biomolecular probes

Important drug targets, such as ion channels and G protein–coupled receptors, are difficult to address using current antibody technologies. Trkulja et al. used kinetically controlled proteases and microfluidic techniques to identify antibody binding sites on native and disease-relevant proteins. Applying molecular level epitope information, the authors were able to produce high-affinity antibodies with programmed pharmacological function. In the article, Trkulja et al. demonstrate the technique by creating the first stimulus-selective monoclonal antibodies targeting the transient receptor potential vanilloid 1 (TRPV1) channel, a clinically validated pain target widely considered undruggable with antibodies. In their research, the authors use Dynaflow Resolve to measure the impact of the antibodies on TRPV1 activity.

Carolina L. Trkulja, Oscar Jungholm, Max Davidson, Kent Jardemark, Monica M. Marcus, Jessica Hägglund, Anders Karlsson, Roger Karlsson, Joseph Bruton, Niklas Ivarsson, Sreesha P. Srinivasa, Alexandra Cavallin, Peder Svensson, Gavin D. M. Jeffries, Maria-Nefeli Christakopoulou,  Anna Reymer, Anaswara Ashok, Gabriella Willman, Daniela Papadia, Emma Johnsson, Owe Orwar

Science Adances. 7, 2021. DOI: 10.1126/sciadv.abe6397 

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Structural basis of α-scorpion toxin action on Nav channels

Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling, but its mechanism remains poorly understood. Researchers at Genentech Inc. used electron microscopy to determine the structure of eukaryotic Nav channel alone and in complex with a lethal α-scorpion toxin (AaH2). The researchers show that AaH2 traps the ion channel in a deactivated state by lodging itself into the voltage-sensing domain of the ion channel, thereby preventing fast deactivation. In their work, the researchers use Dynaflow Resolve to study the activation of different forms of the Nav channel, with and without AaH2 binding.

Thomas Clairfeuille, Alexander Cloake, Daniel T. Infield, José P. Llongueras, Christopher P. Arthur, Zhong Rong Li, Yuwen Jian, Marie-France Martin-Eauclaire, Pierre E. Bougis, Claudio Ciferri, Christopher A. Ahern, Frank Bosmans, David H. Hackos, Alexis Rohou, Jian Payandeh

Science. 363, 2019. DOI: 10.1126/science.aav8573

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ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Smeland et al. report a syndrome in six patients from two families with consistent phenotype, which includes mild intellectual disability, myopathy and cerebral white matter hyperintensities. The patients are homozygous for a mutation that results in non-functional KATP channels in recombinant assay. Loss of function in the SUR2 subunit of KATP channel, which is the area affected by the mutation, is associated with fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. The researchers term this disability resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) In their work, the researchers used Dynaflow Resolve to measure KATP channel activity.

Marie F. Smeland, Conor McClenaghan, Helen I. Roessler, Sanne Savelberg, Geir Åsmund Myge Hansen, Helene Hjellnes, Kjell Arne Arntzen, Kai Ivar Müller, Andreas Rosenberger Dybesland, Theresa Harter, Monica Sala-Rabanal, Chris H. Emfinger, Yan Huang, Soma S. Singareddy, Jamie Gunn, David F. Wozniak, Attila Kovacs, Maarten Massink, Federico Tessadori, Sarah M. Kamel, Jeroen Bakkers, Maria S. Remedi, Marijke Van Ghelue, Colin G. Nichols, Gijs van Haaften

Nature Communications. 10, 2019. DOI: 10.1038/s41467-019-12428-7

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