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- EMDB-16963: Leishmania tarentolae proteasome 20S subunit in complex with 1-Be... -

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Basic information

Entry
Database: EMDB / ID: EMD-16963
TitleLeishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Map data
Sample
  • Complex: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
    • Protein or peptide: x 13 types
  • Protein or peptide: x 1 types
  • Ligand: x 1 types
KeywordsProteasome 20S subunit / UNKNOWN FUNCTION
Function / homology
Function and homology information


proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / proteasomal protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleus / cytoplasm
Similarity search - Function
Proteasome subunit alpha 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature ...Proteasome subunit alpha 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature / Proteasome alpha-type subunits signature. / Proteasome alpha-subunit, N-terminal domain / Proteasome subunit A N-terminal signature Add an annotation / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome B-type subunit / Proteasome beta-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
Proteasome beta 6 subunit, putative / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome alpha 5 subunit, putative / Proteasome subunit alpha type / Proteasome alpha 7 subunit, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta ...Proteasome beta 6 subunit, putative / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome alpha 5 subunit, putative / Proteasome subunit alpha type / Proteasome alpha 7 subunit, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome alpha 1 subunit, putative
Similarity search - Component
Biological speciesLeishmania tarentolae (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsRowland P
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2023
Title: Structure-Guided Design and Synthesis of a Pyridazinone Series of Proteasome Inhibitors.
Authors: Michael G Thomas / Kate McGonagle / Paul Rowland / David A Robinson / Peter G Dodd / Isabel Camino-Díaz / Lorna Campbell / Juan Cantizani / Pablo Castañeda / Daniel Conn / Peter D Craggs / ...Authors: Michael G Thomas / Kate McGonagle / Paul Rowland / David A Robinson / Peter G Dodd / Isabel Camino-Díaz / Lorna Campbell / Juan Cantizani / Pablo Castañeda / Daniel Conn / Peter D Craggs / Darren Edwards / Liam Ferguson / Andrew Fosberry / Laura Frame / Panchali Goswami / Xiao Hu / Justyna Korczynska / Lorna MacLean / Julio Martin / Nicole Mutter / Maria Osuna-Cabello / Christy Paterson / Imanol Peña / Erika G Pinto / Caterina Pont / Jennifer Riley / Yoko Shishikura / Frederick R C Simeons / Laste Stojanovski / John Thomas / Karolina Wrobel / Robert J Young / Filip Zmuda / Fabio Zuccotto / Kevin D Read / Ian H Gilbert / Maria Marco / Timothy J Miles / Pilar Manzano / Manu De Rycker /
Abstract: There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, ...There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the proteasome. A related analogue, active against , showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.
History
DepositionMar 30, 2023-
Header (metadata) releaseAug 9, 2023-
Map releaseAug 9, 2023-
UpdateAug 23, 2023-
Current statusAug 23, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16963.png

Downloads & links

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Map

FileDownload / File: emd_16963.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.22610833 - 0.40274763
Average (Standard dev.)0.00075352343 (±0.013990045)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 321.00003 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Flipped half map to correspond with the final map

Fileemd_16963_half_map_1.map
AnnotationFlipped half map to correspond with the final map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Flipped half map to correspond with the final map

Fileemd_16963_half_map_2.map
AnnotationFlipped half map to correspond with the final map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Leishmania tarentolae proteasome 20S subunit in complex with 1-Be...

EntireName: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Components
  • Complex: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
    • Protein or peptide: Proteasome subunit alpha type
    • Protein or peptide: Proteasome subunit alpha type
    • Protein or peptide: Proteasome subunit alpha type
    • Protein or peptide: Proteasome subunit alpha type
    • Protein or peptide: Proteasome alpha 5 subunit, putative
    • Protein or peptide: Proteasome alpha 1 subunit, putative
    • Protein or peptide: Proteasome alpha 7 subunit, putative
    • Protein or peptide: Proteasome subunit beta
    • Protein or peptide: Proteasome subunit beta
    • Protein or peptide: Proteasome subunit beta
    • Protein or peptide: Proteasome subunit beta
    • Protein or peptide: Proteasome beta 6 subunit, putative
    • Protein or peptide: Proteasome subunit beta
  • Protein or peptide: Proteasome subunit beta
  • Ligand: ~{N}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylmethyl)pyridazine-3-carboxamide

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Supramolecule #1: Leishmania tarentolae proteasome 20S subunit in complex with 1-Be...

SupramoleculeName: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#11, #13-#14
Source (natural)Organism: Leishmania tarentolae (eukaryote)

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Macromolecule #1: Proteasome subunit alpha type

MacromoleculeName: Proteasome subunit alpha type / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 27.178107 KDa
SequenceString: MNRAGFDKYI TVFSPEGSLY QVEYAFKAVT YPGLLTVAIR CKDAVLVVTQ HLIPDRLMRP DSVTALYEVT PNIGCCMTGR APDGRALVQ RAREEASDYQ YRYGVEIPIA VLAKRMGDKA QVRTQQAGLR PMGVVSTFIG MDQSDQDGSL KPQIYTVDPA G WTGGHIAC ...String:
MNRAGFDKYI TVFSPEGSLY QVEYAFKAVT YPGLLTVAIR CKDAVLVVTQ HLIPDRLMRP DSVTALYEVT PNIGCCMTGR APDGRALVQ RAREEASDYQ YRYGVEIPIA VLAKRMGDKA QVRTQQAGLR PMGVVSTFIG MDQSDQDGSL KPQIYTVDPA G WTGGHIAC AAGKKQVEAM AFLEKRQKST ELDALTQKEA AMIALAALQS AIGTAVKAKE VEVGRCTAAN PAFQRVPNSE VE EWLTAVA EAD

UniProtKB: Proteasome subunit alpha type

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Macromolecule #2: Proteasome subunit alpha type

MacromoleculeName: Proteasome subunit alpha type / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 25.179559 KDa
SequenceString: MSEAFYGLTT FSPSGKLIQI EYATTAAGKG TTALGVKATD GVVIAAKKKA PSTLVDASSI QKVFVLDEHV GCTYSGMGPD CRVLIDSAR KNCQQYKLMY NEPIPISQLV RKISAIYQEF TQSGGVRPFG CSLLVAGVDA NGYHLYQVDP SGTFWAWKAT A IGTGSPDA ...String:
MSEAFYGLTT FSPSGKLIQI EYATTAAGKG TTALGVKATD GVVIAAKKKA PSTLVDASSI QKVFVLDEHV GCTYSGMGPD CRVLIDSAR KNCQQYKLMY NEPIPISQLV RKISAIYQEF TQSGGVRPFG CSLLVAGVDA NGYHLYQVDP SGTFWAWKAT A IGTGSPDA KAFLEKRYTV DMELEDAVHT ALLTLKEGFD GQMTSENTQV GRVVENRFEI LSVDQLRDYL DQI

UniProtKB: Proteasome subunit alpha type

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Macromolecule #3: Proteasome subunit alpha type

MacromoleculeName: Proteasome subunit alpha type / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 32.321438 KDa
SequenceString: MSHRYDSRTT TFSPEGRLYQ VEYAVEAIQQ AGTVIGVCTK DGVVLAGEKM VPHPLFDSES MQDKNTSGEK MYKIAEHIGC SVAGVTSDA YALLNYARLS ALRHQYTFQE PMAIEDLCRI LCDEKQLYTQ YGGVRPYGVS FLLVGWDRYY GYQLYSTEPS G DYSAWSAY ...String:
MSHRYDSRTT TFSPEGRLYQ VEYAVEAIQQ AGTVIGVCTK DGVVLAGEKM VPHPLFDSES MQDKNTSGEK MYKIAEHIGC SVAGVTSDA YALLNYARLS ALRHQYTFQE PMAIEDLCRI LCDEKQLYTQ YGGVRPYGVS FLLVGWDRYY GYQLYSTEPS G DYSAWSAY AIGQNDQVAH ALLKKDWHES MTLEDGMLLA LRVLGKTMDT AKIDLDRVEV AVMRKVPASN IDQLLDPFKH HP KTTPRFQ ILTRSELKPH AERADQAREA EEKAEAERQR QQEQALES

UniProtKB: Proteasome subunit alpha type

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Macromolecule #4: Proteasome subunit alpha type

MacromoleculeName: Proteasome subunit alpha type / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 27.821605 KDa
SequenceString: MSYDRAITVF SPDGHLFQVE YAQEAVKKGL AAVGVLGSDS VVIAVEKKSA VKLQDSRTIR KIYKVDANIY LAFAGLSADA RVLINKAQL ECQRFSLNYE DTMDVDMLVR YVAGVQQKST QSGGSRPFGV ATVIGGFNED GKPHLWKTDP SGMCSAWRAV A IGRHDQTV ...String:
MSYDRAITVF SPDGHLFQVE YAQEAVKKGL AAVGVLGSDS VVIAVEKKSA VKLQDSRTIR KIYKVDANIY LAFAGLSADA RVLINKAQL ECQRFSLNYE DTMDVDMLVR YVAGVQQKST QSGGSRPFGV ATVIGGFNED GKPHLWKTDP SGMCSAWRAV A IGRHDQTV IEYMEKSYKD GMSRDECVHF AIKSLLEVVE SGSRNIELLV LQYKEARYLT EEELQKFVVE VEKEREEEAA AK KKRQAEQ E

UniProtKB: Proteasome subunit alpha type

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Macromolecule #5: Proteasome alpha 5 subunit, putative

MacromoleculeName: Proteasome alpha 5 subunit, putative / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 38.312316 KDa
SequenceString: MLLPRLFSFP VCWSRALSLV CVYHVSLSFP SNSRRLCATP LLPLPCLCKL PAGHSPRKRC LFSFLSCFLD LTYFCIISFL HSVSCHLCF PLRRTRARHP IMFTSKSEYD RGVNTFSPEG RIFQIEYAVE AIKLGSTSLG IRTPEGVVLA AEKRVPSTLV V PSSMSKIM ...String:
MLLPRLFSFP VCWSRALSLV CVYHVSLSFP SNSRRLCATP LLPLPCLCKL PAGHSPRKRC LFSFLSCFLD LTYFCIISFL HSVSCHLCF PLRRTRARHP IMFTSKSEYD RGVNTFSPEG RIFQIEYAVE AIKLGSTSLG IRTPEGVVLA AEKRVPSTLV V PSSMSKIM EVDSHIAAVM SGMVADARIL VEHARVESQN HRFTYNEPMS VESCTLATCD LSIQFGESGG RRKLMSRPFG VS LLIAGVD EKGPQLWQTD PSGTHTRYDA QAIGGGAEAA QSVFTERYHR NMTLEEGETL AVDILKQVME DQLSPENIEV AVV RADDGK LHMYTPTEIK AIMSRMPE

UniProtKB: Proteasome alpha 5 subunit, putative

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Macromolecule #6: Proteasome alpha 1 subunit, putative

MacromoleculeName: Proteasome alpha 1 subunit, putative / type: protein_or_peptide / ID: 6 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 47.978633 KDa
SequenceString: MQSRKGEGWR DTGTDSLPPF SFCCSPAFSS PLAFGGEGAD GCAYILTHVC RYACIAALTL HSEGAERHMR VCVCVRRCAY NEMVLHQVV AFASLAPALH PLSPLPLPCM ATTHACCGLR VRSFSLKKSE KKNQQRRLQA PDLSQKTRTR TQKEKQTLQI Y LRCVMFKN ...String:
MQSRKGEGWR DTGTDSLPPF SFCCSPAFSS PLAFGGEGAD GCAYILTHVC RYACIAALTL HSEGAERHMR VCVCVRRCAY NEMVLHQVV AFASLAPALH PLSPLPLPCM ATTHACCGLR VRSFSLKKSE KKNQQRRLQA PDLSQKTRTR TQKEKQTLQI Y LRCVMFKN EYDSDITTWS PTGRLFQIEY ANEAVNNGSA TVGVKGKNFV VLAALKRSPV AELSSYQEKV FEIDEHVGMS IS GLVADGR VLARYLRTEC MNYRYMYSNG MPMNQMADMI GEKHQRHIQC SGKRPFGVGL LLAGYDRQGP HLYQTVPSGD VYD YKATAM GVRSQASRTY LERHFEHFSD CTLDELVTHA LKALASATSE GIELNVKNTT IAIVGKDTPF TIFEEESARK YLDG FKMRP EDRVAVAEED EEMLHEQPLD VEE

UniProtKB: Proteasome alpha 1 subunit, putative

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Macromolecule #7: Proteasome alpha 7 subunit, putative

MacromoleculeName: Proteasome alpha 7 subunit, putative / type: protein_or_peptide / ID: 7 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 25.591826 KDa
SequenceString: MAGTGSGHDQ STDVFSAEGR VFQVEYAGKA VDNSSTAVAA CCKDGVVVAV EKVHTSRMLE KGSNNRIHAV DRQAGICICG LLPDGRAIV SRARQEAENS RDIFATPIRG SVLANRVGEF MHAYTTHFAY RPFGCSAIIA SYADDGPQLF VSDPSGTVAG Y YGVALGKA ...String:
MAGTGSGHDQ STDVFSAEGR VFQVEYAGKA VDNSSTAVAA CCKDGVVVAV EKVHTSRMLE KGSNNRIHAV DRQAGICICG LLPDGRAIV SRARQEAENS RDIFATPIRG SVLANRVGEF MHAYTTHFAY RPFGCSAIIA SYADDGPQLF VSDPSGTVAG Y YGVALGKA KTVAKSELEK LDFSSLTCDE AVGKLASILH EVHDKQKDKL YEVEVAWVCD KSDRKFVHVP ADMVPAETSH

UniProtKB: Proteasome alpha 7 subunit, putative

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Macromolecule #8: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 8 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 30.28001 KDa
SequenceString: MLQRPDHTLL QEPAYPKDIA QKLTENGPAQ AGKQLFQPDP AVIDPQLSKA VSLGTTILAV SYNGGVVLAA DSRTSSGTYV VNRASNKLT KLTKKIYCCR SGSAADTQAL AERVSNYLGS YQTDIGAGVN VATAANLFQK MCYMNRWNIS AGIIVAGYDP I NGGSVYSI ...String:
MLQRPDHTLL QEPAYPKDIA QKLTENGPAQ AGKQLFQPDP AVIDPQLSKA VSLGTTILAV SYNGGVVLAA DSRTSSGTYV VNRASNKLT KLTKKIYCCR SGSAADTQAL AERVSNYLGS YQTDIGAGVN VATAANLFQK MCYMNRWNIS AGIIVAGYDP I NGGSVYSI PSGGSCVKLD YALGGSGSIF LYSFFDANYK PGMSKSECVA FCQRAVAHAY SRDGSSGGLI RTITLDADEP ED QTIPWNR SPYCMEKDPK YVTQATQNQP FSSSAKITGN RMSSTG

UniProtKB: Proteasome subunit beta

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Macromolecule #9: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 9 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 27.60357 KDa
SequenceString: MPGFNFENVQ RNLNLEGEGY SAPRTLKTGT TIVGVVYRDG VVLGADTRAT EGSIVADKRC RKIHYMAPNI MCCGAGTSAD TEAVTNMVS SHLALHRLET GKQSRVLEAL TLLKRHLYRY QGHVSAALVL GGVDVEGPFL ATIAPHGSTD RLPFVTMGSG S IAAMAQLE ...String:
MPGFNFENVQ RNLNLEGEGY SAPRTLKTGT TIVGVVYRDG VVLGADTRAT EGSIVADKRC RKIHYMAPNI MCCGAGTSAD TEAVTNMVS SHLALHRLET GKQSRVLEAL TLLKRHLYRY QGHVSAALVL GGVDVEGPFL ATIAPHGSTD RLPFVTMGSG S IAAMAQLE AAYKDNMTCE EAKELVASAI RKGIFNDPYS GTQVDVCVIT KDKTELTIGY DKPNERMYPR QEVLLPPGTT PV LKEEIRQ LVDIVDA

UniProtKB: Proteasome subunit beta

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Macromolecule #10: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 10 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 22.470887 KDa
SequenceString: MSIMAYSGGS VMAMAGKECF VIISDNRLGE QLKTISTEVP KLHVVNDSIV YGLTGLRTDQ QTFANKVQFR TEMYKLREER DITGKAFAA MITSMLYEAR FGPWFVEPVI GSIDKSTGEV YLCATDLIGA PCEPEDYVCA GTAAESLHGM CEALWRPGMS P EELFEIAA ...String:
MSIMAYSGGS VMAMAGKECF VIISDNRLGE QLKTISTEVP KLHVVNDSIV YGLTGLRTDQ QTFANKVQFR TEMYKLREER DITGKAFAA MITSMLYEAR FGPWFVEPVI GSIDKSTGEV YLCATDLIGA PCEPEDYVCA GTAAESLHGM CEALWRPGMS P EELFEIAA QAMLSACDRD SLSGYGAVAM IVTKDKVTTR LIKGRKD

UniProtKB: Proteasome subunit beta

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Macromolecule #11: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 11 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 23.065291 KDa
SequenceString: MAETAIAFRC KDYVMVAAAG LNAFYYIKIT DAEDKITQLD THQLVACTGE NGPRVNFTEY IKCNLALNRM RQHGRHSSCE STANFMRNC LASAIRSREG AYQVNCLFAG YDTPVSEDDD GVVGPQLFYM DYLGTLQAVP YGCHGYGACF VTALLDRLWR P DLSQQEGL ...String:
MAETAIAFRC KDYVMVAAAG LNAFYYIKIT DAEDKITQLD THQLVACTGE NGPRVNFTEY IKCNLALNRM RQHGRHSSCE STANFMRNC LASAIRSREG AYQVNCLFAG YDTPVSEDDD GVVGPQLFYM DYLGTLQAVP YGCHGYGACF VTALLDRLWR P DLSQQEGL ELMQKCCDEV KRRVIISNSY FFVKAVTKNG VEVITAVH

UniProtKB: Proteasome subunit beta

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Macromolecule #12: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 12 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 33.576738 KDa
SequenceString: MFADFEAVTS SNFTLDDCPR VGPFTYHNMD EDTLEEPLSL CSYRRAPQQT DERSPASCDA VTADPLDSSR YLHGENRCWT LKVSCPVPR AIPKLDMKKG TTTLAFRFNG GIIVAVDSRA STGQYIASQT VMKVLEINDY LLGTLAGGAA DCQYWERVLG M ECRLWELR ...String:
MFADFEAVTS SNFTLDDCPR VGPFTYHNMD EDTLEEPLSL CSYRRAPQQT DERSPASCDA VTADPLDSSR YLHGENRCWT LKVSCPVPR AIPKLDMKKG TTTLAFRFNG GIIVAVDSRA STGQYIASQT VMKVLEINDY LLGTLAGGAA DCQYWERVLG M ECRLWELR NGSRITVAAA SKILANITYA YRNHGLSMGT MVAGWDQFGP SLYYVDDKGS RVKQDLFSVG SGSIYAYGVL DT GYRKDLS VEDACDLARR SIFHATYRDG ASGGIVTVYH VHEKGWTKIS RDDQTKLYHR YFPS

UniProtKB: Proteasome subunit beta

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Macromolecule #13: Proteasome beta 6 subunit, putative

MacromoleculeName: Proteasome beta 6 subunit, putative / type: protein_or_peptide / ID: 13 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 37.67691 KDa
SequenceString: MASSSPPLLP FSSFVVAVVA IHLSFRVFCV GAQSLCKCCS CVPACALPLC FSSSPSVSAE DVALALFAHP KVLTHRPTAR YSPILSLLH YAVMIEDHAE YGHNYYPQKL ASSTLTLPQQ GAKQQQWSPY QDNGGTTAAI AGKDFVILAG DTRLNGDFCL H SRHDQSKI ...String:
MASSSPPLLP FSSFVVAVVA IHLSFRVFCV GAQSLCKCCS CVPACALPLC FSSSPSVSAE DVALALFAHP KVLTHRPTAR YSPILSLLH YAVMIEDHAE YGHNYYPQKL ASSTLTLPQQ GAKQQQWSPY QDNGGTTAAI AGKDFVILAG DTRLNGDFCL H SRHDQSKI FQLTPYTYMA SNGMQADRLQ LQQMLKYRVK WYKYNNGGKV PSTKAIAQLM STMLYHRRFF PYYTFNMVVG LD EEGHGVC YSYDAVGSTE PFLYGTRGSA ASFVEPLLDC LINRQHMTSQ APPEMTKEET LAMLKNAFTG AAERDIYTGD SVS FFIITK DGVQQESFEL RKD

UniProtKB: Proteasome beta 6 subunit, putative

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Macromolecule #14: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 14 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Molecular weightTheoretical: 24.737232 KDa
SequenceString: MASGGSVIAI KYKGGVLMAA DTLLSYGSLA KWPNIPRIRL LGSHSAVCAT GSYADFQMMA KQVEDNIERQ KMYHNVDELS PSEVFSYLH RSIYQKRCDF DPCLCQMVFI GVRDGETFLA GVDDVGTRWE DDCIATGYGA YIALPLLRQA LEKNPDGLSR G EAMRILTD ...String:
MASGGSVIAI KYKGGVLMAA DTLLSYGSLA KWPNIPRIRL LGSHSAVCAT GSYADFQMMA KQVEDNIERQ KMYHNVDELS PSEVFSYLH RSIYQKRCDF DPCLCQMVFI GVRDGETFLA GVDDVGTRWE DDCIATGYGA YIALPLLRQA LEKNPDGLSR G EAMRILTD CLRVLFYREC RAINKFQVAD AASDGVRISE PFDVETHWEY EGYCFEKTAI IR

UniProtKB: Proteasome subunit beta

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Macromolecule #15: ~{N}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylme...

MacromoleculeName: ~{N}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylmethyl)pyridazine-3-carboxamide
type: ligand / ID: 15 / Number of copies: 2 / Formula: VYW
Molecular weightTheoretical: 388.419 Da
Chemical component information

ChemComp-VYW:
~{N}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylmethyl)pyridazine-3-carboxamide

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.4 µm / Nominal defocus min: 1.8 µm
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 30.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 94595
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: Other / Chain - Initial model type: experimental model / Details: Unpublished model
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-8olu:
Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

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