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- PDB-9l3f: Structure-Guided Design of Picomolar-level Macrocyclic TRPC5 Chan... -

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Basic information

Entry
Database: PDB / ID: 9l3f
TitleStructure-Guided Design of Picomolar-level Macrocyclic TRPC5 Channel Inhibitors with Antidepressant Activity
ComponentsShort transient receptor potential channel 5
KeywordsMEMBRANE PROTEIN / Ion channel / TRPC5 / Inhibitor
Function / homology
Function and homology information


regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / store-operated calcium channel activity / TRP channels / inositol 1,4,5 trisphosphate binding / cation channel complex / actinin binding / clathrin binding / regulation of cytosolic calcium ion concentration ...regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / store-operated calcium channel activity / TRP channels / inositol 1,4,5 trisphosphate binding / cation channel complex / actinin binding / clathrin binding / regulation of cytosolic calcium ion concentration / positive regulation of axon extension / positive regulation of neuron differentiation / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / neuron differentiation / presynapse / actin binding / growth cone / ATPase binding / positive regulation of cytosolic calcium ion concentration / neuron apoptotic process / neuronal cell body / positive regulation of cell population proliferation / dendrite / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 5 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential channel, canonical 5 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
: / Short transient receptor potential channel 5
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsChe, T. / Zhang, J. / Xiong, B. / Cheng, X.Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32271260 China
CitationJournal: Acta Pharm Sin B / Year: 2026
Title: Structure-guided design of picomolar-level macrocyclic TRPC5 channel inhibitors with antidepressant activity.
Authors: Tong Che / Yixiang Chen / Xinyu Cheng / Han Hu / Xiaoyun Wu / Yuting Zhang / Xiaoqiang Yang / Yinzhen Liu / Hui Liu / Weiwei Nan / Shuangyan Wan / Mingxing Yang / Bo Zeng / Jian Li / Jin Zhang / Bing Xiong /
Abstract: Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets-often large and flat-remain a major hurdle for developing selective ...Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets-often large and flat-remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC of 374 pmol/L-200-fold more potent than HC-070-and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimizing activity against related TRPC channels and other ion channels. This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders. The study demonstrates how macrocycles stabilize ligand conformations, enhance affinity, and achieve selectivity in lipid-dominated binding sites. It also highlights the synergy between macrocyclic design, cryo-EM, and computational modeling to address longstanding obstacles in ion channel drug discovery. JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology, offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond, with implications for a wide range of diseases.
History
DepositionDec 18, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 24, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Dec 24, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 18, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Short transient receptor potential channel 5
B: Short transient receptor potential channel 5
C: Short transient receptor potential channel 5
D: Short transient receptor potential channel 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)358,20916
Polymers355,6154
Non-polymers2,59412
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Short transient receptor potential channel 5 / TrpC5 / Capacitative calcium entry channel 2 / CCE2 / Transient receptor protein 5 / TRP-5 / mTRP5 ...TrpC5 / Capacitative calcium entry channel 2 / CCE2 / Transient receptor protein 5 / TRP-5 / mTRP5 / Trp-related protein 5


Mass: 88903.672 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpc5, Trp5, Trrp5 / Production host: Homo sapiens (human) / References: UniProt: Q9QX29
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-A1EH7 / (E)-1-(4-chlorobenzyl)-3-fluoro-1-(3-hydroxypropyl)-1,1,1,1-tetrahydro-1H-2,4-dioxa-1(8,3)-purina-3(1,3)-benzenacyclodecaphane-1,1-dione


Mass: 542.986 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H28ClFN4O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Short transient receptor potential channel 5 / Type: CELL / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50.53 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 128115 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00323148
ELECTRON MICROSCOPYf_angle_d0.55631396
ELECTRON MICROSCOPYf_dihedral_angle_d12.07913756
ELECTRON MICROSCOPYf_chiral_restr0.043508
ELECTRON MICROSCOPYf_plane_restr0.0053916

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