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- PDB-7lw1: Human phosphofructokinase-1 liver type bound to activator NA-11 -

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Basic information

Entry
Database: PDB / ID: 7lw1
TitleHuman phosphofructokinase-1 liver type bound to activator NA-11
ComponentsATP-dependent 6-phosphofructokinase, liver type
KeywordsTRANSFERASE / glycolysis / phosphofructokinase / liver type / activated
Function / homology
Function and homology information


6-phosphofructokinase complex / 6-phosphofructokinase / fructose binding / 6-phosphofructokinase activity / fructose-6-phosphate binding / fructose 1,6-bisphosphate metabolic process / fructose 6-phosphate metabolic process / canonical glycolysis / Glycolysis / response to glucose ...6-phosphofructokinase complex / 6-phosphofructokinase / fructose binding / 6-phosphofructokinase activity / fructose-6-phosphate binding / fructose 1,6-bisphosphate metabolic process / fructose 6-phosphate metabolic process / canonical glycolysis / Glycolysis / response to glucose / glycolytic process / negative regulation of insulin secretion / kinase binding / secretory granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / extracellular exosome / extracellular region / ATP binding / metal ion binding / identical protein binding / membrane / cytosol
Similarity search - Function
ATP-dependent 6-phosphofructokinase, vertebrate-type / ATP-dependent 6-phosphofructokinase, eukaryotic-type / Phosphofructokinase domain / Phosphofructokinase, conserved site / Phosphofructokinase signature. / Phosphofructokinase domain / ATP-dependent 6-phosphofructokinase / Phosphofructokinase superfamily / Phosphofructokinase / Rossmann fold ...ATP-dependent 6-phosphofructokinase, vertebrate-type / ATP-dependent 6-phosphofructokinase, eukaryotic-type / Phosphofructokinase domain / Phosphofructokinase, conserved site / Phosphofructokinase signature. / Phosphofructokinase domain / ATP-dependent 6-phosphofructokinase / Phosphofructokinase superfamily / Phosphofructokinase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / 6-O-phosphono-beta-D-fructofuranose / 1,6-di-O-phosphono-beta-D-fructofuranose / Chem-YG1 / ATP-dependent 6-phosphofructokinase, liver type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLynch, E.M. / Kollman, J.M. / Webb, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM118396 United States
CitationJournal: Cell / Year: 2021
Title: Selective activation of PFKL suppresses the phagocytic oxidative burst.
Authors: Neri Amara / Madison P Cooper / Maria A Voronkova / Bradley A Webb / Eric M Lynch / Justin M Kollman / Taylur Ma / Kebing Yu / Zijuan Lai / Dewakar Sangaraju / Nobuhiko Kayagaki / Kim Newton ...Authors: Neri Amara / Madison P Cooper / Maria A Voronkova / Bradley A Webb / Eric M Lynch / Justin M Kollman / Taylur Ma / Kebing Yu / Zijuan Lai / Dewakar Sangaraju / Nobuhiko Kayagaki / Kim Newton / Matthew Bogyo / Steven T Staben / Vishva M Dixit /
Abstract: In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading ...In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.
History
DepositionFeb 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: ATP-dependent 6-phosphofructokinase, liver type
D: ATP-dependent 6-phosphofructokinase, liver type
E: ATP-dependent 6-phosphofructokinase, liver type
F: ATP-dependent 6-phosphofructokinase, liver type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)346,19720
Polymers340,4824
Non-polymers5,71616
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
ATP-dependent 6-phosphofructokinase, liver type / ATP-PFK / PFK-L / 6-phosphofructokinase type B / Phosphofructo-1-kinase isozyme B / PFK-B / Phosphohexokinase


Mass: 85120.375 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PFKL / Production host: unidentified baculovirus / References: UniProt: P17858, 6-phosphofructokinase
#2: Chemical
ChemComp-YG1 / N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide


Mass: 401.458 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H23N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Sugar
ChemComp-FBP / 1,6-di-O-phosphono-beta-D-fructofuranose / BETA-FRUCTOSE-1,6-DIPHOSPHATE / FRUCTOSE-1,6-BISPHOSPHATE / 1,6-di-O-phosphono-beta-D-fructose / 1,6-di-O-phosphono-D-fructose / 1,6-di-O-phosphono-fructose


Type: D-saccharide, beta linking / Mass: 340.116 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H14O12P2
IdentifierTypeProgram
b-D-Fruf1PO36PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#4: Sugar
ChemComp-F6P / 6-O-phosphono-beta-D-fructofuranose / FRUCTOSE-6-PHOSPHATE / 6-O-phosphono-beta-D-fructose / 6-O-phosphono-D-fructose / 6-O-phosphono-fructose


Type: D-saccharide, beta linking / Mass: 260.136 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H13O9P
IdentifierTypeProgram
b-D-Fruf6PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#5: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestY

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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: Human phosphofructokinase-1 liver type bound to activator NA-11
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: unidentified baculovirus
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2800 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 10 sec. / Electron dose: 90 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2529
Image scansWidth: 3710 / Height: 3838 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

EM software
IDNameVersionCategory
4CTFFIND4CTF correction
7ISOLDE1model fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
12RELION3.13D reconstruction
13ISOLDE1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3000000
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 63296 / Symmetry type: POINT

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