THE MINOR LAB Home of the Electrosome

Research Interests

[1] Structural Understanding of Ion Channel Action and Regulation

Propagation of electrical signals in the cardiac and nervous systems requires the concerted action of ion channel proteins and the molecules that modulate their activity. Understanding ion channels ultimately requires a high-resolution structural description of the channel proteins, their regulatory factors, and the conformational changes that accompany channel action. Our lab approaches this problem from the perspective of structural biology. Because channels are membrane proteins, a difficult class to investigate with any single structural technique, our efforts are directed at a multidisciplinary approach that involves a breadth of methods such as X-ray crystallography, cyro-electronmicroscopy, chemical approaches, and genetics for studying ion channel structure and function. Our current research aims to understand the central types of channels that are responsible for excitation (voltage-gated calcium channels and voltage-gated sodium channels) and inhibition (potassium channels) of electrical activity.

Key Publications

A selectivity filter gate controls voltage gated calcium channel (CaV) calcium-dependent inactivation. Abderemane-Ali, F., Findeisen, F., Rossen, N.D., and Minor, D.L. Jr., Neuron 101 1134-1149 (2019) PMID: 30733149 PMCID.

A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function. Chang, A., Abderemane-Ali, F., Hura, G.L., Rossen, N.D., Gate, R.E., Minor, D.L., Jr., Neuron 97 836-852 (2018) View Video Abstract PMID:29429937 PMCID: PMC5823783

K2P2.1(TREK-1):activator complexes reveal a cryptic selectivity filter binding site. Lolicato, M., Arrigoni, C., Mori, T., Sekioka, Y., Bryant, C., Clark, K.A., Minor, D.L., Jr., Nature 547 364-368 (2017) PMID: 28693035 PMCID: PMC5778891

Unfolding of a temperature-sensitive domain controls voltage-gated channel activation. Arrigoni, C., Rohaim, A., Shaya, D., Findeisen, F., Stein, R.A. Nurva, S.R., Mishra, S., Mchaourab, H.S., and Minor, D.L., Jr., Cell 164 922‑936 (2016) PMID: 26919429 PMCID:PMC4769381

Transmembrane helix straightening and buckling underlies activation of mechanosensitive and thermosensitive K2P channels. Lolicato, M., Riegelhaupt, P.M., Arrigoni, C., Clark, K.A., Minor, D.L., Jr., Neuron 84 1198‑1212 (2014) PMID: 25500157 PMCID: PMC4270892

Multiple modalities act through a common gate to control K2P channel function. Bagriantsev, S., Clark, K.A., Peyronnet, R., Honoré, E., and Minor, D.L., Jr., The EMBO Journal 30 3594-3606 (2011)

Structure of a complex between a voltage‑gated calcium channel β-subunit and an α-subunit domain. Van Petegem, F., Clark, K.A., Chatelain, F.C., and Minor, D.L., Jr., Nature 429 671-675 (2004) PMID:15141227

UCSF Minor Lab Research

[2] Ion Channel Chemical Biology

A rich diversity of ion channel genes and families are now known from molecular cloning and genome sequencing efforts. This abundance of ion channel genes poses dual problems: most have unknown functions and few have defined pharmacologies that can be used to dissect their biophysical or physiological mechanisms of action. Indeed, there are entire channel families that remain effectively pharmacological orphans. Unraveling the functions of this multitude of ion channels demands the development of new chemical biology tools that can be used to control the action of a given ion channel in both in vivo and in vitro settings.

We are pursing a range of approaches to create and develop new protein-based and small molecule-based ion channel modulators that will expand the repertoire of novel ion channel-directed chemical biology agents. Our efforts deploy genetic selection methods to generate high affinity, specific inhibitors and activators of ion channels through the use of molecular evolution and selection methods (Bagriantsev et al. 2013, 2014), structure-based design of protein-protein interaction inhibitors (Findeisen et al, 2017), and structure-based development of ion channel small molecule modulators (Lolicato, et. al. Nature, 2017). These new tools should aid in unlocking unlock a wide range of currently unaddressable questions ranging from basic channel biophysics to physiology.

Key Publications

Protein and chemical determinants of BL-1249 action and selectivity for K2P channels. Pope. L., Arrigoni, C., Lou, H., Bryant, C. Gallardo-Gadoy, A., Renslo, A.R., and Minor, D.L. Jr., ACS Chemical Neuroscience 9 3153-3165, (2018) PMID: 30089357 PMCID: PMC6302903

K2P2.1(TREK-1):activator complexes reveal a cryptic selectivity filter binding site. Lolicato, M., Arrigoni, C., Mori, T., Sekioka, Y., Bryant, C., Clark, K.A., Minor, D.L., Jr., Nature 547 364-368 (2017) PMID: 28693035 PMCID: PMC5778891

Stapled voltage-gated calcium channel (CaV) α-Interaction Domain (AID) peptides act as selective protein-protein interaction inhibitors of CaV Function. Findeisen, F., Campiglio, M., Jo, H., Abderemane-Ali, F., Rumpf, C.H., Pope, L., Rossen, N.D., Flucher, B.E., DeGrado, W.F., and Minor D.L., Jr., ACS Chemical Neuroscience 8 1313-1326 (2017) PMID: 28278376 PMCID: PMC5481814

Tethered protein display identifies a novel Kir3.2 (GIRK2) regulator from protein scaffold libraries. Bagriantsev, S.N., Chatelain, F.C., Clark, K.A., Alagem, N., Reuveny, E., Minor, D.L., Jr., ACS Chemical Neuroscience 5 812‑822 (2014) PMID: 25028803 PMCID: PMC4176385

A high-throughput functional screen identifies small molecule regulators or temperature- and mechano-sensitive K2P channels. Bagriantsev, S. N., Ang, K.H., Gallardo-Godoy, A, Clark, K.A., Arkin, M.R., Renslo, A.R, and Minor, D.L., Jr,. ACS Chemical Biology 8 1841-1851 (2013) PMID: 23738709PMCID: PMC3747594

[3] Molecular mechanisms of toxin resistance

Many small molecule toxins act on ion channels. One of the most lethal is saxitoxin (STX). This paralytic neurotoxin is produced by oceanic red tides inhibits voltage-gated sodium channels (NaVs) and has the unusual distinction of being the only marine toxin declared a biological weapon. STX causes of paralytic shellfish poisoning (PSP) and poses a significant public health and commercial hazard that is increasing from the effects of climate change. Remarkably, some organisms appear to have the ability to resist the effects STX and other toxins by deploying ‘molecular sponge’ toxin binding proteins. We want to understand the molecular mechanisms that underly this ability to resist toxic environments. Our initial studies of saxiphilin, a soluble high affinity STX binding protein from the American bullfrog show that the STX recognition mechanism is related to the way the toxin interacts with NaVs. Uncovering how saxiphilin and other toxin binding proteins recognize and neutralize lethal toxins should bring fundamental understanding of the molecular recognition code for sequestering small molecule toxins. Such advances will empower the development of new detection systems for environmental toxins and may lead to new means to mitigate STX poisoning.

Key PublicationsPRESS

Structure of the saxiphilin:saxitoxin (STX)complex reveals a convergent molecular recognition strategy for paralytic toxins. Yen, T.-J., Lolicato, M., Thomas-Tran, R., Du Bois, J., and Minor, D.L. Jr., Science Advances 5 eaax2650 (2019) PMID: 31223657 PMCID: PMC6584486

Additional Press

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