About

Eduardo Perozo, PhD, is the Lillian Eichelberger Cannon Professor of Biochemistry and Molecular Biology at the University of Chicago. He is also a professor of Neuroscience and serves on the Institute Committee on Computational Neuroscience and the Committee on Neurobiology. His research focuses on the structural and functional mechanisms of ion channels, including the pore structure of the Shaker K+ channel, the allosteric activation gating of BK channels, and potassium-dependent structural changes in HERG channels. Additionally, his work explores the folding mechanisms of prestin related to outer hair cell electromotility, the behavior of voltage-sensing domains in proteins like Ci-VSP, and the functional states of ion channels such as CorA and MscS. Dr. Perozo's contributions advance understanding of ion channel gating, conformational states, and membrane protein mechanisms, contributing significantly to the fields of biochemistry, molecular biology, and neuroscience.

Research topics

• Chemistry
• Biology
• Biophysics
• Anatomy
• Computer Science
• Cell biology
• Biochemistry
• Ecology
• Genetics
• Stereochemistry
• Computer network
• Pharmacology
• Neuroscience

Selected publications

• Conformational ensembles of the magnesium channel CorA reveal structural basis for channel gating

  Proceedings of the National Academy of Sciences · 2026-02-17 · 1 citations

  articleOpen accessCorresponding

  In prokaryotes, CorA is the primary influx pathway for magnesium, a critical divalent cation in cellular physiology and biochemistry. Mechanistic studies show that homopentameric CorA is regulated through an intracellular [Mg 2+ ]-dependent negative feedback loop, involving the asymmetric participation of individual subunits. To understand the connection between asymmetry and activation, we used single-particle cryo-EM to solve sixteen structures of nanodisc-reconstituted CorA. We utilized conformation-specific synthetic antibodies to stabilize subtle but significant conformational differences in the cryo-EM structures. Our results demonstrate that CorA exists as a set of conformational ensembles, where population size inversely correlates with intracellular Mg 2+ concentration. These ensembles include channels with a variety of pore conformations, both constricted and dilated, suggesting a spectrum of active CorA functional states. The ensembles connect asymmetric structural transitions in the cytoplasmic domain with conformational changes in the permeation pathway via an electrostatic network, ultimately controlling channel-gating events. We believe that these results establish a framework for understanding magnesium homeostasis in prokaryotic systems.

  PublisherDOI

• The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating

  Proceedings of the National Academy of Sciences · 2026-01-27

  articleOpen accessCorresponding

  BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore's open conformation remain unclear. Using cryoelectron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within a pocket formed by the S6/RCK1 linker and the S4 transmembrane segment. Our simulations suggest that agonist binding promotes a twisting motion in the S6 segment, enabling critical interactions with residues K330, K331, and F223. These findings provide a molecular model for the mechanism of NS1619 and suggest that its binding site can accommodate other agonists, highlighting a promising target for therapeutic development.

  PublisherDOI

• BPS2026 – The closed pore and intermediate voltage sensor of the shaker potassium channel: Electromechanical coupling

  Biophysical Journal · 2026-02-01

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  PublisherDOI

• BPS2026 – Flipping gating polarity in hERG by uncoupling the S4-S5 linker from the inner bundle gate

  Biophysical Journal · 2026-02-01

  articleSenior author
  PublisherDOI

• Closed State Structure of the Pore Revealed by Uncoupled Shaker K ⁺ Channel

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-17

  preprintOpen access

  Voltage gated potassium (Kv) channels play key roles in numerous physiological processes from cellular excitability to immune response and are among the most important pharmaceutical targets. Despite recent advances in the structural determination of Kv channels, the closed state structure of strictly coupled Kv1 family remains elusive. Here, we captured the closed state structure of the pore in the Shaker potassium by uncoupling the voltage sensor domains from the pore domains. Ionic current, gating current and fluorescence measurements show that a conserved isoleucine residue in the S4-S5 linker region, plays a key role controlling the strength of the electromechanical coupling and the channel activation-deactivation equilibrium. Structural determination of completely uncoupled I384R mutant by single particle cryoEM revealed a fully closed pore in the presence of fully activated but non-relaxed voltage sensors. The putative conformational transitions from a fully open pore domain indicates a "roll and turn" movement along the whole length of the pore-forming S6 helices in sharp contrast to canonical gating models based on limited movements of S6. The rotational and translational movement posits two hydrophobic residues, one at inner cavity and the other at the bundle crossing region, directly at the permeation pathway, limiting the pore radius to less than 0.7Å. Voltage clamp fluorimetry of wild type channel incorporating a fluorescent unnatural amino acid strongly supports the cryoEM structural model. Surprisingly, the selectivity filter was captured in a noncanonical state, unlike the previously described dilated or pinched filter conformations. With the present experiment results, we propose a new gating model for strictly coupled Kv1 channels and the molecular mechanism of interactions among different functional states.

  PublisherOA PDFDOI

• BPS2025 - Collective effects of prestin in high frequency amplification by outer hair cells

  Biophysical Journal · 2025-02-01

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  PublisherDOI

• BPS2025 - A key residue in S4-S5 linker controls electromechanical coupling in Kv channels

  Biophysical Journal · 2025-02-01

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  PublisherDOI

• Structure of the ILT Mutant Shaker K ⁺ Channel and the Mechanism of Voltage Activation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-14

  preprintOpen access

  Voltage-gated potassium (Kv) channels play a critical role in cellular excitability and the propagation of the nerve impulse. Despite the extensive amount of information available about Kv channels, the complete process of voltage activation-where a conformational change mediated by voltage-sensor domains (VSD) opens the intracellular gate in response to the depolarization of the membrane potential-has not been fully elucidated. To understand this process, we study the Kv Shaker channel and focus on the ILT mutant (V369I, I372L, S376T) known to display a long-lived closed intermediate state during the activation process. Single particle CryoEM of the ILT mutant reveals a novel conformation of Shaker in which the intracellular gate formed by the S5-S6 helices is in a closed state and the S4 helix in the VSD is in an intermediate state shifted down by ~5Å relative to its position in the fully activated open channel. Additional conformations of the channel generated by Alphafold2 and molecular dynamics simulations are used to map the sequence of intermediate states along the voltage activation process, revealing the nature of the couping between the VSD, the S4-S5 linker, and the S5-S6 intracellular gate. In the final stage of the activation process, as the VSD reaches its fully activated conformation while the gate remains closed, essential interactions between the S4-S5 linker and the intracellular S5-S6 gate are transiently disrupted and reformed when the gate opens, demonstrating that electro-mechanical coupling results from a dynamic shift in population equilibrium between metastable states. These findings provide unprecedented mechanistic insight into how structural rearrangements underlie the voltage activation process in Kv channels, offering broader implications for understanding channelopathies and designing targeted modulators.

  PublisherOA PDFDOI

• Structural basis of voltage-dependent gating in BK channels

  Nature Communications · 2025-07-01 · 10 citations

  articleOpen accessSenior author

  Abstract The allosteric communication between the pore domain, voltage sensors, and Ca 2+ binding sites in the calcium- and voltage-activated K + channel (BK) underlies its physiological role as the preeminent signal integrator in excitable systems. BK displays shallow voltage sensitivity with very fast gating charge kinetics, yet little is known about the molecular underpinnings of this distinctive behavior. Here, we explore the mechanistic basis of coupling between voltage-sensing domains (VSDs) and calcium sensors in Aplysia BK by locking the VSDs in their activated (R196Q and R199Q) and resting (R202Q) states, with or without calcium. Cryo-EM structures of these mutants reveal unique tilts at the S4 C-terminal end, together with large side-chain rotameric excursions of the gating charges. Notably, the VSD resting structure (R202Q) also revealed BK in its elusive, fully closed state, highlighting the reciprocal relation between calcium and voltage sensors. These structures provide a plausible path where voltage and Ca 2+ binding couple energetically and define the conformation of the pore domain and, thus, BK’s full functional range.

  PublisherDOI

• Structural Mechanism of Prestin-Membrane Mechanotransduction

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-01 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Sound frequency discrimination in mammals depends on the conformational transitions of prestin (SLC26A5), the piezoelectric motor in outer hair cells. The mechanism that enables prestin's electrically driven interconversion and its dependence on membrane mechanics, remains unresolved. Here, we show that membrane forces represent a strong driver of the same conformational changes generated by transmembrane voltage and stabilized by bound anions. Single particle cryo-EM structures of nanodisc-reconstituted prestin were obtained from varying lipid composition and membrane thickness. These structures show that membrane thinning biases prestin from a compact conformation to a fully expanded conformation, mimicking outer hair cell elongation/contraction during electromotility. In contrast, zebrafish SLC26A5 transporters undergo complete elevator movements with redistribution of areal changes across leaflets. The structures, together with mutagenesis, H/D exchange mass spectrometry data, and NLC measurements, offer a high-resolution understanding of how prestin translates membrane tension into charge and motor movement during sound-evoked vibrations, revealing a process of reciprocal electro-mechanical transduction essential for tuning cochlear amplification.

  PublisherOA PDFDOI

Recent grants

• High Resolution Structural Dynamics of K Channels

  NIH · $7.9M · 1998–2020

• NIH Grant R01GM088406

  NIH · $1.3M · 2014

• NIH Grant U54GM087519

  NIH · $63.6M · 2019

• Structural basis of Mg2+ homeostasis

  NIH · $1.4M · 2017–2021

• NIH Grant R01GM063617

  NIH · $2.1M · 2010

Frequent coauthors

• D. Marien Cortés

  Texas Tech University Health Sciences Center

  77 shared

• Luis G. Cuello

  Texas Tech University Health Sciences Center

  54 shared

• Benoı̂t Roux

  University of Chicago

  51 shared

• Valeria Vásquez

  The University of Texas Health Science Center at Houston

  48 shared

• Julio F. Cordero-Morales

  The University of Texas Health Science Center at Houston

  47 shared

• Qufei Li

  University of Chicago

  43 shared

• Francisco Bezanilla

  University of Valparaíso

  37 shared

• Sherry Wanderling

  Howard Hughes Medical Institute

  32 shared