Home > Publications

Influences: Russian training

Published on 01.06.2019

Journal of General Physiology

I grew up in Yaroslavl, an old Russian city on the Volga River, which celebrated its 1,000th anniversary in 2010. Because my mom, a medical nurse, and my dad, a railroad worker, belonged to the working class, I had no intentions of becoming a scientist. As a kid, I dreamed about becoming many things, from […]


Mechanisms of channel block in calcium-permeable AMPA receptors

Published on 08.16.2018

Neuron

We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping block.


Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB

Published on 06.23.2018

Nature Communications

Using a combination of X-ray crystallography, cryo-electron microscopy, and functional recordings of calcium flux through TRPV6 and other TRPV ion channels, we have identified a new ligand binding site by which these ion channels can be regulated.


X-ray crystallography of TRP channels

Published on 04.30.2018

Taylor and Francis

Transient receptor potential (TRP) ion channels are molecular sensors of a large variety of stimuli including temperature, mechanical stress, voltage, small molecules including capsaicin and menthol, and lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). Since the same TRP channels may respond to different physical and chemical stimuli, they can serve as signal integrators.


Ion permeation mechanism in epithelial calcium channel TRVP6

Published on 04.09.2018

Scientific Reports

At low Ca2+ concentrations, only a single calcium ion binds at the narrow constriction of the TRPV6 selectivity filter formed by aspartates D541 and allows Na+ permeation. During ion permeation, no water crosses the channel pore narrow constriction. At high Ca2+ concentrations, calcium permeates the pore according to the knock-off mechanism that includes formation of a short-lived transition state with three calcium ions bound near D541.


Opening of the human epithelial calcium channel TRPV6

Published on 12.20.2017

Nature

Here we present cryo-electron microscopy structures of human TRPV6 in the open and closed states. The channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an α-to-π-helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter.


Structural mechanisms of gating in ionotropic glutamate receptors

Published on 10.16.2017

Biochemistry

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the central nervous system. iGluRs open their ion channels in response to binding of the neurotransmitter glutamate, rapidly depolarize the postsynaptic neuronal membrane, and initiate signal transduction.


Swapping of transmembrane domains in the epithelial calcium channel TRPV6

Published on 09.06.2017

Scientific Reports

Here we show that mutations in the transmembrane domain of TRPV6 can result in conversion from a domain-swapped to non-swapped fold. These results reveal structural determinants of domain swapping and raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states.


Determining the crystal structure of TRPV6

Published on 06.08.2017

Taylor and Francis

The concept of signal transduction is now long established as a central tenet of biological sciences. Since the inception of the field close to 50 years ago, the number and variety of signal transduction pathways, cascades, and networks have steadily increased and now constitute what is often regarded as a bewildering array of mechanisms by which cells sense and respond to extracellular and intracellular environmental stimuli.


Structural bases of desensitization in AMPA receptor-auxiliary subunit complexes

Published on 05.03.2017

Neuron

Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry.


Role of the ion channel extracellular collar in AMPA receptor gating

Published on 04.21.2017

Scientific Reports

We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating.


Structural bases of noncompetitive inhibition of AMPA-subtype ionotropic glutamate receptors by antiepileptic drugs

Published on 09.08.2016

Neuron

Here, we report crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors. The inhibitors bind to a novel binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains. We propose that the inhibitors stabilize the AMPA receptor closed state.


Elucidation of AMPA receptor-stargazin complexes by cryo-electron microscopy

Published on 07.01.2016

Science

Here, we used cryo-electron microscopy to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2, or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR.


Structure of an agonist-bound ionotropic glutamate receptor

Published on 08.29.2014

Science

Here, we report a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-nitrowillardiine. Comparison of this structure with the closed-state structure in complex with competitive antagonist ZK 200775 suggests conformational changes that occur during iGluR gating.


Block of AMPA receptor desensitization by a point mutation outside the ligand-binding domain

Published on 05.19.2004

The Journal of Neuroscience logo

Abstract Desensitization of ionotropic glutamate receptors (GluRs), specifically the AMPA receptor subtype, shapes the postsynaptic response at certain synapses in the brain. All known mechanisms that alter desensitization, either pharmacological or mutational, are associated with the ligand-binding domain. Here we report that substitution of a conserved positively charged arginine (R) with a negatively charged glutamate […]


Different gating mechanisms in glutamate receptor and K+ channels

Published on 08.20.2003

The Journal of Neuroscience logo

The basic structural features of channel gating in glutamate receptors (GluRs) remain unknown. Here we used covalent modification of substituted cysteines and fast agonist application to study the contribution of the M3 segment in AMPA receptor GluR-A subunits to channel structure and gating.