Antibodies and venom peptides: new modalities for ion channels

Wulff, Heike; Christophersen, Palle; Colussi, Paul A.; Chandy, K. George; Yarov‐Yarovoy, Vladimir

doi:10.1038/s41573-019-0013-8

Cited by 144 publications

(132 citation statements)

References 197 publications

(281 reference statements)

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“…In contrast, TRPC5 inhibitors show promise for the treatment of central nervous system (CNS) diseases and focal segmental glomerulosclerosis (FSGS) in animal models ( 26-28 ). A TRPC4/5 inhibitor developed by Hydra and Boehringer Ingelheim is in clinical trial for the treatment of anxiety disorder and depression ( 29 ). Another TRPC5 inhibitor GFB-887 developed by Goldfinch Bio is currently in phase 1 clinical trial for the treatment of kidney disease (NCT number: NCT03970122).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Song

Wei

Guo

et al. 2020

Preprint

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17TRPC5 channel is a non-selective cation channel that participates diverse physiological 18 processes. Human TRPC5 inhibitors show promise in the treatment of anxiety disorder, 19 depression and kidney disease. Despite the high relevance of TRPC5 to human health, its 20 inhibitor binding pockets have not been fully characterized due to the lack of structural 21 information, which greatly hinders structure-based drug discovery. Here we show cryo-EM 22 structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and 23 HC-070, to the resolution of 2.7 Å. Based on the high-quality cryo-EM maps, we uncover the 24 different binding pockets and detailed binding modes for these two inhibitors. Clemizole 25 binds inside the voltage sensor-like domain of each subunit, while HC-070 binds close to the 26 ion channel pore and is wedged between adjacent subunits. Both of them exert the inhibitory 27 function by stabilizing the ion channel in a closed state. These structures provide templates 28 for further design and optimization of inhibitors targeting human TRPC5. 29 70 inhibitory mechanism of these two distinct inhibitors against human TRPC5 (hTRPC5), we 71 embarked structural studies of hTRPC5 in complex with CMZ or HC-070. Our high 72 resolution cryo-EM maps are sufficient to identify their binding pockets and will aid further 73 drug development. 74 75 76 Results 77 78 Structure of human TRPC5 in complex with inhibitors 79To reveal the binding sites of CMZ and HC-070 on hTRPC5, we expressed hTRPC5 in 80 HEK293F cells for structural studies. Similar to the mouse TRPC5 counterpart (mTRPC5) 81 (33), C-terminal truncation of hTRPC5 generated a construct (hTRPC5 1-764 ) that showed 82 higher expression level of the tetramer in comparison with the full length wild type hTRPC5 83 ( Fig. S1A). Moreover, we found hTRPC5 1-764 retained the pharmacological properties of full 84 length hTRPC5 such as activation by EA ( Fig. S1, B to E). Therefore, we used hTRPC5 1-764 85 protein for structural studies. Tetrameric hTRPC5 1-764 channel was purified in detergent 86 micelles (Fig. S1F and G). To obtain the CMZ-bound and the HC-070-bound TRPC5 87 structures, CMZ or HC-070 was added to the concentrated hTRPC5 1-764 protein for cryo-EM 88 sample preparation. We obtained maps of hTRPC5 in CMZ-bound state and HC-070-bound 89 state to the resolution of 2.7 Å (Fig. 1, Figs. S2 to S5; table S1). The map qualities were 90 sufficient for model building and ligand assignment (Fig. S3, D and E, and Fig. S5, D and E).91The overall architecture of inhibitor-bound hTRPC5 is similar to the structure of mTRPC5 in 92 apo state (33), occupying 100 Å × 100 Å × 130 Å in three-dimensional space (Fig. 1). The 93 four-fold symmetric channel has two layer architecture, composed of the intracellular 94 cytosolic domain (ICD) layer and the transmembrane domain (TMD) layer (Fig. 1). In ICD 95 layer, the N-terminal ankyrin repeats domain (ARD) is below the linker-helix domain (LHD) 96 region (Fig .1F). The TRP helix mediates interactions...

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Section: Introductionmentioning

confidence: 99%

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Song

Wei

Guo

et al. 2020

Preprint

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“…Blockers of Kv1.3 and other potassium channels have been found in the venom of numerous animals, including the venom of anemone (Wulff et al, 2019). In 1995, an effective K + channel blocker was extracted from the sea anemone (S. helianthus) by Castaneda et al (1995) and then named it ShK (Wulff and Zhorov, 2008).…”

Section: Multiple Sclerosismentioning

confidence: 99%

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Wang

Guo

et al. 2020

Front. Neurosci.

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“…The modulators usually belong to one of three major categories: metal ions, organic small molecules, and venom-derived peptides. Peptides and peptidomimetics are important candidates as potent and specific inhibitors, 81 but lack of selectivity limits the applicability of the first two groups.…”

Section: Potassium Channels In Cancermentioning

confidence: 99%

“…82 Nevertheless, to date, only one ion channel antibody-based therapy has reached the level of clinical trials; this is a polyclonal sheep antibody against a nonfunctional form of P2X7, which is being evaluated for topical treatment of basal cell carcinoma. 81,83 The selectivity and specificity of antibodies against K V channels can be also used for diagnostic and prognostic purposes, but we will limit our description to therapeutic strategies in cancer. The therapeutic potential of antibodies against ion channels in general has recently been exhaustively reviewed elsewhere.…”

Section: Potassium Channels In Cancermentioning

confidence: 99%

Antibodies Targeting K_VPotassium Channels: A Promising Treatment for Cancer

2019

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Voltage-gated potassium channels are transmembrane proteins that allow flow of potassium across the membrane to regulate ion homeostasis, cell proliferation, migration, cell volume, and specific processes such as muscular contraction. Aberrant function or expression of potassium channels can underlie pathologies ranging from heart arrhythmia to cancer; the expression of potassium channels is altered in many types of cancer and that alteration correlates with malignancy and poor prognosis. Targeting potassium channels therefore constitutes a promising approach for cancer therapy. In this review, we discuss strategies to target a particular family of potassium channels, the voltage-gated potassium channels (K V) where a reasonable structural understanding is available. We also discuss the possible obstacles and advantages of such a strategy.

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Antibodies and venom peptides: new modalities for ion channels

Cited by 144 publications

References 197 publications

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Antibodies Targeting K_VPotassium Channels: A Promising Treatment for Cancer

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Antibodies and venom peptides: new modalities for ion channels

Cited by 144 publications

References 197 publications

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Antibodies Targeting KVPotassium Channels: A Promising Treatment for Cancer

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Antibodies Targeting K_VPotassium Channels: A Promising Treatment for Cancer