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- EMDB-43046: Full length integrin AlphaIIbBeta3 in pre-active state -

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Basic information

Entry
Database: EMDB / ID: EMD-43046
TitleFull length integrin AlphaIIbBeta3 in pre-active state
Map data
Sample
  • Complex: The extracellular domain of integrin AlphaIIbBeta3 in pre-active state
    • Protein or peptide: Integrin alpha-IIb
    • Protein or peptide: Integrin beta-3
Keywordsintegrin / CELL ADHESION
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.46 Å
AuthorsHuo T / Wu H / Wang Z
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL162842 United States
CitationJournal: Structure / Year: 2024
Title: Full-length αIIbβ3 cryo-EM structure reveals intact integrin initiate-activation intrinsic architecture.
Authors: Tong Huo / Hongjiang Wu / Zeinab Moussa / Mehmet Sen / Valerie Dalton / Zhao Wang /
Abstract: Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length ...Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3 Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show conformational changes of the αIIbβ3 activating trajectory and a unique twisting of the integrin legs, which is required for platelets accumulation. Our structure provides direct structural evidence for how the lower legs are involved in full-length integrin activation mechanisms and offers a new strategy to target the αIIbβ3 lower leg.
History
DepositionDec 6, 2023-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43046.png

Downloads & links

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Map

FileDownload / File: emd_43046.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.219
Minimum - Maximum-0.4042253 - 0.667278
Average (Standard dev.)-0.00047742427 (±0.028196516)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 342.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43046_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43046_half_map_2.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 : The extracellular domain of integrin AlphaIIbBeta3 in pre-active state

EntireName: The extracellular domain of integrin AlphaIIbBeta3 in pre-active state
Components
  • Complex: The extracellular domain of integrin AlphaIIbBeta3 in pre-active state
    • Protein or peptide: Integrin alpha-IIb
    • Protein or peptide: Integrin beta-3

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Supramolecule #1: The extracellular domain of integrin AlphaIIbBeta3 in pre-active state

SupramoleculeName: The extracellular domain of integrin AlphaIIbBeta3 in pre-active state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Integrin alpha-IIb

MacromoleculeName: Integrin alpha-IIb / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString: MARALCPLQA LWLLEWVLLL LGPCAAPPAW ALNLDPVQLT FYAGPNGSQF GFSLDFHKDS HGRVAIVVG APRTLGPSQE ETGGVFLCPW RAEGGQCPSL LFDLRDETRN VGSQTLQTFK A RQGLGASV VSWSDVIVAC APWQHWNVLE KTEEAEKTPV GSCFLAQPES ...String:
MARALCPLQA LWLLEWVLLL LGPCAAPPAW ALNLDPVQLT FYAGPNGSQF GFSLDFHKDS HGRVAIVVG APRTLGPSQE ETGGVFLCPW RAEGGQCPSL LFDLRDETRN VGSQTLQTFK A RQGLGASV VSWSDVIVAC APWQHWNVLE KTEEAEKTPV GSCFLAQPES GRRAEYSPCR GN TLSRIYV ENDFSWDKRY CEAGFSSVVT QAGELVLGAP GGYYFLGLLA QAPVADIFSS YRP GILLWH VSSQSLSFDS SNPEYFDGYW GYSVAVGEFD GDLNTTEYVV GAPTWSWTLG AVEI LDSYY QRLHRLRGEQ MASYFGHSVA VTDVNGDGRH DLLVGAPLYM ESRADRKLAE VGRVY LFLQ PRGPHALGAP SLLLTGTQLY GRFGSAIAPL GDLDRDGYND IAVAAPYGGP SGRGQV LVF LGQSEGLRSR PSQVLDSPFP TGSAFGFSLR GAVDIDDNGY PDLIVGAYGA NQVAVYR AQ PVVKASVQLL VQDSLNPAVK SCVLPQTKTP VSCFNIQMCV GATGHNIPQK LSLNAELQ L DRQKPRQGRR VLLLGSQQAG TTLNLDLGGK HSPICHTTMA FLRDEADFRD KLSPIVLSL NVSLPPTEAG MAPAVVLHGD THVQEQTRIV LDCGEDDVCV PQLQLTASVT GSPLLVGADN VLELQMDAA NEGEGAYEAE LAVHLPQGAH YMRALSNVEG FERLICNQKK ENETRVVLCE L GNPMKKNA QIGIAMLVSV GNLEEAGESV SFQLQIRSKN SQNPNSKIVL LDVPVRAEAQ VE LRGNSFP ASLVVAAEEG EREQNSLDSW GPKVEHTYEL HNNGPGTVNG LHLSIHLPGQ SQP SDLLYI LDIQPQGGLQ CFPQPPVNPL KVDWGLPIPS PSPIHPAHHK RDRRQIFLPE PEQP SRLQD PVLVSCDSAP CTVVQCDLQE MARGQRAMVT VLAFLWLPSL YQRPLDQFVL QSHAW FNVS SLPYAVPPLS LPRGEAQVWT QLLRALEERA IPIWWVLVGV LGGLLLLTIL VLAMWK VGF FKRNRPPLEE DDEEGE

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Macromolecule #2: Integrin beta-3

MacromoleculeName: Integrin beta-3 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString: MRARPRPRPL WATVLALGAL AGVGVGGPNI CTTRGVSSCQ QCLAVSPMCA WCSDEALPLG SPRCDLKEN LLKDNCAPES IEFPVSEARV LEDRPLSDKG SGDSSQVTQV SPQRIALRLR P DDSKNFSI QVRQVEDYPV DIYYLMDLSY SMKDDLWSIQ NLGTKLATQM ...String:
MRARPRPRPL WATVLALGAL AGVGVGGPNI CTTRGVSSCQ QCLAVSPMCA WCSDEALPLG SPRCDLKEN LLKDNCAPES IEFPVSEARV LEDRPLSDKG SGDSSQVTQV SPQRIALRLR P DDSKNFSI QVRQVEDYPV DIYYLMDLSY SMKDDLWSIQ NLGTKLATQM RKLTSNLRIG FG AFVDKPV SPYMYISPPE ALENPCYDMK TTCLPMFGYK HVLTLTDQVT RFNEEVKKQS VSR NRDAPE GGFDAIMQAT VCDEKIGWRN DASHLLVFTT DAKTHIALDG RLAGIVQPND GQCH VGSDN HYSASTTMDY PSLGLMTEKL SQKNINLIFA VTENVVNLYQ NYSELIPGTT VGVLS MDSS NVLQLIVDAY GKIRSKVELE VRDLPEELSL SFNATCLNNE VIPGLKSCMG LKIGDT VSF SIEAKVRGCP QEKEKSFTIK PVGFKDSLIV QVTFDCDCAC QAQAEPNSHR CNNGNGT FE CGVCRCGPGW LGSQCECSEE DYRPSQQDEC SPREGQPVCS QRGECLCGQC VCHSSDFG K ITGKYCECDD FSCVRYKGEM CSGHGQCSCG DCLCDSDWTG YYCNCTTRTD TCMSSNGLL CSGRGKCECG SCVCIQPGSY GDTCEKCPTC PDACTFKKEC VECKKFDRGA LHDENTCNRY CRDEIESVK ELKDTGKDAV NCTYKNEDDC VVRFQYYEDS SGKSILYVVE EPECPKGPDI L VVLLSVMG AILLIGLAAL LIWKLLITIH DRKEFAKFEE ERARAKWDTA NNPLYKEATS TF TNITYRG T

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175020
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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