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Yorodumi- EMDB-23544: Human phosphofructokinase-1 liver type bound to activator NA-11 -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23544 | |||||||||
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Title | Human phosphofructokinase-1 liver type bound to activator NA-11 | |||||||||
Map data | Human phosphofructokinase-1 liver type bound to activator NA-11 | |||||||||
Sample |
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Keywords | glycolysis / phosphofructokinase / liver type / activated / TRANSFERASE | |||||||||
Function / homology | Function and homology information fructose binding / 6-phosphofructokinase complex / 6-phosphofructokinase / 6-phosphofructokinase activity / fructose-6-phosphate binding / fructose 6-phosphate metabolic process / monosaccharide binding / canonical glycolysis / fructose 1,6-bisphosphate metabolic process / Glycolysis ...fructose binding / 6-phosphofructokinase complex / 6-phosphofructokinase / 6-phosphofructokinase activity / fructose-6-phosphate binding / fructose 6-phosphate metabolic process / monosaccharide binding / canonical glycolysis / fructose 1,6-bisphosphate metabolic process / Glycolysis / AMP binding / negative regulation of insulin secretion / response to glucose / glycolytic process / kinase binding / secretory granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / extracellular exosome / extracellular region / ATP binding / identical protein binding / membrane / metal ion binding / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Lynch EM / Kollman JM | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23544.map.gz | 11 MB | EMDB map data format | |
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Header (meta data) | emd-23544-v30.xml emd-23544.xml | 14.5 KB 14.5 KB | Display Display | EMDB header |
Images | emd_23544.png | 238.3 KB | ||
Filedesc metadata | emd-23544.cif.gz | 6.2 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23544 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23544 | HTTPS FTP |
-Validation report
Summary document | emd_23544_validation.pdf.gz | 384.5 KB | Display | EMDB validaton report |
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Full document | emd_23544_full_validation.pdf.gz | 384.1 KB | Display | |
Data in XML | emd_23544_validation.xml.gz | 6.6 KB | Display | |
Data in CIF | emd_23544_validation.cif.gz | 7.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23544 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23544 | HTTPS FTP |
-Related structure data
Related structure data | 7lw1MC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23544.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Human phosphofructokinase-1 liver type bound to activator NA-11 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.05 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Human phosphofructokinase-1 liver type bound to activator NA-11
Entire | Name: Human phosphofructokinase-1 liver type bound to activator NA-11 |
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Components |
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-Supramolecule #1: Human phosphofructokinase-1 liver type bound to activator NA-11
Supramolecule | Name: Human phosphofructokinase-1 liver type bound to activator NA-11 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: ATP-dependent 6-phosphofructokinase, liver type
Macromolecule | Name: ATP-dependent 6-phosphofructokinase, liver type / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: 6-phosphofructokinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 85.120375 KDa |
Recombinant expression | Organism: unidentified baculovirus |
Sequence | String: MAAVDLEKLR ASGAGKAIGV LTSGGDAQGM NAAVRAVTRM GIYVGAKVFL IYEGYEGLVE GGENIKQANW LSVSNIIQLG GTIIGSARC KAFTTREGRR AAAYNLVQHG ITNLCVIGGD GSLTGANIFR SEWGSLLEEL VAEGKISETT ARTYSHLNIA G LVGSIDND ...String: MAAVDLEKLR ASGAGKAIGV LTSGGDAQGM NAAVRAVTRM GIYVGAKVFL IYEGYEGLVE GGENIKQANW LSVSNIIQLG GTIIGSARC KAFTTREGRR AAAYNLVQHG ITNLCVIGGD GSLTGANIFR SEWGSLLEEL VAEGKISETT ARTYSHLNIA G LVGSIDND FCGTDMTIGT DSALHRIMEV IDAITTTAQS HQRTFVLEVM GRHCGYLALV SALASGADWL FIPEAPPEDG WE NFMCERL GETRSRGSRL NIIIIAEGAI DRNGKPISSS YVKDLVVQRL GFDTRVTVLG HVQRGGTPSA FDRILSSKMG MEA VMALLE ATPDTPACVV TLSGNQSVRL PLMECVQMTK EVQKAMDDKR FDEATQLRGG SFENNWNIYK LLAHQKPPKE KSNF SLAIL NVGAPAAGMN AAVRSAVRTG ISHGHTVYVV HDGFEGLAKG QVQEVGWHDV AGWLGRGGSM LGTKRTLPKG QLESI VENI RIYGIHALLV VGGFEAYEGV LQLVEARGRY EELCIVMCVI PATISNNVPG TDFSLGSDTA VNAAMESCDR IKQSAS GTK RRVFIVETMG GYCGYLATVT GIAVGADAAY VFEDPFNIHD LKVNVEHMTE KMKTDIQRGL VLRNEKCHDY YTTEFLY NL YSSEGKGVFD CRTNVLGHLQ QGGAPTPFDR NYGTKLGVKA MLWLSEKLRE VYRKGRVFAN APDSACVIGL KKKAVAFS P VTELKKDTDF EHRMPREQWW LSLRLMLKML AQYRISMAAY VSGELEHVTR RTLSMDKGF UniProtKB: ATP-dependent 6-phosphofructokinase, liver type |
-Macromolecule #2: N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,...
Macromolecule | Name: N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide type: ligand / ID: 2 / Number of copies: 4 / Formula: YG1 |
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Molecular weight | Theoretical: 401.458 Da |
Chemical component information | ChemComp-YG1: |
-Macromolecule #3: 1,6-di-O-phosphono-beta-D-fructofuranose
Macromolecule | Name: 1,6-di-O-phosphono-beta-D-fructofuranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: FBP |
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Molecular weight | Theoretical: 340.116 Da |
Chemical component information | ChemComp-FBP: |
-Macromolecule #4: 6-O-phosphono-beta-D-fructofuranose
Macromolecule | Name: 6-O-phosphono-beta-D-fructofuranose / type: ligand / ID: 4 / Number of copies: 4 / Formula: F6P |
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Molecular weight | Theoretical: 260.136 Da |
Chemical component information | ChemComp-F6P: |
-Macromolecule #5: ADENOSINE-5'-DIPHOSPHATE
Macromolecule | Name: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 4 / Formula: ADP |
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Molecular weight | Theoretical: 427.201 Da |
Chemical component information | ChemComp-ADP: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Grid | Model: C-flat-2/2 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3838 pixel / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 2529 / Average exposure time: 10.0 sec. / Average electron dose: 90.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |