A5017476562- Glaucoma and retinal disorders
- Ion channel regulation and function
- Corneal surgery and disorders
- Cardiac electrophysiology and arrhythmias
- Crystallization and Solubility Studies
- Retinal and Optic Conditions
- Nicotinic Acetylcholine Receptors Study
- Retinal Diseases and Treatments
- Cellular transport and secretion
- Ocular Surface and Contact Lens
- Ophthalmology and Eye Disorders
- Enzyme Structure and Function
- Optical Coherence Tomography Applications
- Cerebral Venous Sinus Thrombosis
- Intraocular Surgery and Lenses
- Drug-Induced Ocular Toxicity
- RNA and protein synthesis mechanisms
- Electrochemical Analysis and Applications
- X-ray Diffraction in Crystallography
- Retinal Development and Disorders
- Corneal Surgery and Treatments
- Ocular Diseases and Behçet’s Syndrome
- Microtubule and mitosis dynamics
- Retinal and Macular Surgery
- Neuroscience and Neuropharmacology Research
Shandong Eye Hospital
2010-2025
Shandong First Medical University
2017-2025
Lanzhou University
2025
Xi'an Jiaotong University
2025
Center for Life Sciences
2012-2024
Tsinghua University
2013-2024
Weatherford College
2024
Liaocheng People's Hospital
2024
Doheny Eye Institute
2013-2020
University of California, Los Angeles
2020
TAL (transcription activator-like) effectors, secreted by phytopathogenic bacteria, recognize host DNA sequences through a central domain of tandem repeats. Each repeat comprises 33 to 35 conserved amino acids and targets specific base pair using two hypervariable residues [known as variable diresidues (RVDs)] at positions 12 13. Here, we report the crystal structures an 11.5-repeat effector in both DNA-free DNA-bound states. helices connected short RVD-containing loop. The 11.5 repeats form...
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. They associated with a variety channelopathies targeted by multiple pharmaceutical drugs natural toxins. Here, we report cryogenic electron microscopy structure putative Nav channel from American cockroach (designated NavPaS) at 3.8 angstrom resolution. The voltage-sensing domains (VSDs) four repeats exhibit distinct conformations. entrance to asymmetric selectivity filter vestibule...
Structures of voltage-gated sodium channels In “excitable” cells, like neurons and muscle a difference in electrical potential is used to transmit signals across the cell membrane. This regulated by opening or closing ion For example, mutations human (Na v ) are associated with disorders such as chronic pain, epilepsy, cardiac arrhythmia. Pan et al. report high-resolution structure Na channel, Shen structures an insect channel bound toxins that cause pufferfish shellfish poisoning humans....
Gating a calcium channel The type 2 ryanodine receptor (RyR2) controls the release of ions from sarcoplasmic reticulum in cardiac cells—the initiating step muscle contraction. Mutations RyR2 are associated with diseases. Peng et al. used single-particle electron cryomicroscopy to determine structure porcine heart at 4.4-Å resolution closed and 4.2-Å open. structures reveal how interdomain motions result conformational change cytoplasmic region that is transduced by central domain cause open...
Targeting sodium channels Voltage-gated (Na v ) have been implicated in cardiac and neurological disorders. There are many subtypes of these channels, making it challenging to develop specific therapeutics. A core α subunit is sufficient for voltage sensing ion conductance, but function modulated by β subunits natural toxins that can either act as pore blockers or gating modifiers (see the Perspective Chowdhury Chanda). Shen et al. present structures Na 1.7 complex with both β1 β2 animal...
Animal toxins that modulate the activity of voltage-gated sodium (Nav) channels are broadly divided into two categories-pore blockers and gating modifiers. The pore tetrodotoxin (TTX) saxitoxin (STX) responsible for puffer fish shellfish poisoning in humans, respectively. Here, we present structures insect Nav channel NavPaS bound to a modifier toxin Dc1a at 2.8 angstrom-resolution presence TTX or STX 2.6-Å 3.2-Å resolution, inserts cleft between VSDII NavPaS, making key contacts with both...
A dual stimulus-responsive mPEG-SS-PLL(15)-glutaraldehyde star (mPEG-SS-PLL(15)-star) catiomer is developed and biologically evaluated. The system combines redox-sensitive removal of an external PEG shell with acid-induced escape from the endosomal compartment. design rationale for to augment intracellular uptake mPEG-SS-PLL(15)-star/DNA complexes in presence tumor-relevant glutathione (GSH) concentration, while dissociation accelerate release genetic payload following successful...
Nav 1.5, the primary voltage-gated Na+ (Nav ) channel in heart, is a major target for class I antiarrhythmic agents. Here we present cryo-EM structure of full-length human 1.5 bound to quinidine, Ia drug, at 3.3 Å resolution. Quinidine positioned right beneath selectivity filter pore domain and coordinated by residues from repeats I, III, IV. Pore blockade quinidine achieved through both direct obstruction ion permeation path induced rotation an invariant Tyr residue that tightens...
Among the nine subtypes of human voltage-gated sodium (Nav) channels, brain and cardiac isoforms, Nav1.1 Nav1.5, each carry more than 400 missense mutations respectively associated with epilepsy disorders. High-resolution structures are required for structure-function relationship dissection disease variants. We report cryo-EM full-length Nav1.1-β4 complex at 3.3 Å resolution here Nav1.5-E1784K variant in accompanying paper. Up to 341 261 disease-related respectively, resolved. Comparative...
Abstract The human SLC26 transporter family exhibits various transport characteristics, and member SLC26A9 performs multiple roles, including acting as Cl – /HCO 3 exchangers, channels, Na + transporters. Some mutations of are correlated with abnormalities in respiration digestion systems. As a potential target colocalizing CFTR cystic fibrosis patients, is great value drug development. Here, we present cryo-EM structure the dimer at 2.6 Å resolution. A segment C-terminal end bound to entry...
The dorsal root ganglia-localized voltage-gated sodium (Nav) channel Nav1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of is the requirement more depolarized membrane potential activation. Here we present cryogenic electron microscopy structures human alone and bound to selective pore blocker, A-803467, at overall resolutions 2.7 3.2 Å. first voltage-sensing domain (VSDI) displays three different conformations. Structure-guided...
Significance Dysfunction of Na v 1.5, the primary cardiac channel, is associated with multiple arrhythmia syndromes, exemplified by type 3 long QT syndrome (LQT3) and Brugada (BrS). Establishment structure-function relationship mechanistic understanding disease variants will facilitate development antiarrhythmic drugs. Here we report cryo-EM structure human 1.5-E1784K, most common variant shared LQT3 BrS. Structural mapping 91 LQT3-associated mutations reveal a hotspot that involves fast...
Nav1.7 represents a preeminent target for next-generation analgesics its critical role in pain sensation. Here we report 2.2-Å resolution cryo-EM structure of wild-type (WT) complexed with the β1 and β2 subunits that reveals several previously indiscernible cytosolic segments. Reprocessing data our reported structures Nav1.7(E406K) bound to various toxins identifies two distinct conformations S6IV, one composed α helical turns only other containing π turn middle. The ligand-free...
Voltage-gated sodium (Na v ) channel Na 1.7 has been targeted for the development of nonaddictive pain killers. Structures in distinct functional states will offer an advanced mechanistic understanding and aid drug discovery. Here we report cryoelectron microscopy analysis a human variant that, with 11 rationally introduced point mutations, markedly right-shifted activation voltage curve V 1/2 reaching 69 mV. The voltage-sensing domain first repeat (VSD I 2.7-Å resolution structure displays...
Abstract Voltage-gated sodium (Na v ) channels are targeted by a number of widely used and investigational drugs for the treatment epilepsy, arrhythmia, pain, other disorders. Despite recent advances in structural elucidation Na channels, binding mode most -targeting remains unknown. Here we report high-resolution cryo-EM structures human 1.7 treated with lead compounds representative chemical backbones at resolutions 2.6-3.2 Å. A site beneath intracellular gate (site BIG) accommodates...
Abstract Urate, the physiological form of uric acid and a potent antioxidant in serum, plays pivotal role scavenging reactive oxygen species. Yet excessive accumulation urate, known as hyperuricemia, is primary risk factor for development gout. The high-capacity urate transporter GLUT9 represents promising target gout treatment. Here, we present cryo-electron microscopy structures human complex with or its inhibitor apigenin at overall resolutions 3.5 Å 3.3 Å, respectively. In both...
NaChBac, the first bacterial voltage-gated Na + (Na v ) channel to be characterized, has been prokaryotic prototype for studying structure–function relationship of channels. Discovered nearly two decades ago, structure NaChBac not determined. Here we present single particle electron cryomicroscopy (cryo-EM) analysis in both detergent micelles and nanodiscs. Under conditions, conformation is identical that potentially inactivated Ab. Determining nanodiscs enabled us examine gating modifier...