+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23916 | ||||||||||||
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Title | The HER2/HER3/NRG1b Heterodimer | ||||||||||||
Map data | Main map from non-uniform refinement in cryosparc, filtered to 2.92A in resolution and sharpened with a b-factor of 94.3. | ||||||||||||
Sample |
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Function / homology | Function and homology information neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway ...neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / regulation of microtubule-based process / ErbB-3 class receptor binding / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / semaphorin receptor complex / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / motor neuron apoptotic process / PLCG1 events in ERBB2 signaling / neuromuscular junction development / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / positive regulation of Rho protein signal transduction / detection of maltose stimulus / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / enzyme-linked receptor protein signaling pathway / positive regulation of transcription by RNA polymerase I / maltose transport complex / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / oligodendrocyte differentiation / growth factor binding / carbohydrate transport / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / carbohydrate transmembrane transporter activity / positive regulation of cell adhesion / maltose binding / lateral plasma membrane / maltose transport / maltodextrin transmembrane transport / positive regulation of protein targeting to membrane / regulation of angiogenesis / coreceptor activity / negative regulation of signal transduction / Schwann cell development / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / extrinsic apoptotic signaling pathway in absence of ligand / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cell surface receptor protein tyrosine kinase signaling pathway / GRB2 events in ERBB2 signaling / myelination / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Downregulation of ERBB2:ERBB3 signaling / transmembrane receptor protein tyrosine kinase activity / ATP-binding cassette (ABC) transporter complex / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / phosphatidylinositol 3-kinase/protein kinase B signal transduction / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / cell chemotaxis / positive regulation of epithelial cell proliferation / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / neuron differentiation / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Downregulation of ERBB2 signaling / ruffle membrane / peptidyl-tyrosine phosphorylation / transmembrane signaling receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / myelin sheath Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) / Escherichia coli (E. coli) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.93 Å | ||||||||||||
Authors | Diwanji D / Trenker R / Verba KA / Jura N | ||||||||||||
Funding support | United States, Germany, 3 items
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Citation | Journal: Nature / Year: 2021 Title: Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface. Authors: Devan Diwanji / Raphael Trenker / Tarjani M Thaker / Feng Wang / David A Agard / Kliment A Verba / Natalia Jura / Abstract: Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact ...Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2-HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2-HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2-HER3 and HER2(S310F)-HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)-HER3-NRG1β-trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2-HER3 heterodimer. The unique features of a singly liganded HER2-HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface. | ||||||||||||
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_23916.map.gz | 168 MB | EMDB map data format | |
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Header (meta data) | emd-23916-v30.xml emd-23916.xml | 22.1 KB 22.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23916_fsc.xml | 12.6 KB | Display | FSC data file |
Images | emd_23916.png | 136 KB | ||
Masks | emd_23916_msk_1.map | 178 MB | Mask map | |
Others | emd_23916_half_map_1.map.gz emd_23916_half_map_2.map.gz | 165.4 MB 165.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23916 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23916 | HTTPS FTP |
-Validation report
Summary document | emd_23916_validation.pdf.gz | 878.9 KB | Display | EMDB validaton report |
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Full document | emd_23916_full_validation.pdf.gz | 878.4 KB | Display | |
Data in XML | emd_23916_validation.xml.gz | 20 KB | Display | |
Data in CIF | emd_23916_validation.cif.gz | 25.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23916 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23916 | HTTPS FTP |
-Related structure data
Related structure data | 7mn5MC 7mn6C 7mn8C 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_23916.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Main map from non-uniform refinement in cryosparc, filtered to 2.92A in resolution and sharpened with a b-factor of 94.3. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23916_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Half-map B
File | emd_23916_half_map_1.map | ||||||||||||
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Annotation | Half-map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half-map A
File | emd_23916_half_map_2.map | ||||||||||||
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Annotation | Half-map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : HER2/HER3/NRG1b Heterocomplex in the context of near full-length ...
Entire | Name: HER2/HER3/NRG1b Heterocomplex in the context of near full-length receptors |
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Components |
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-Supramolecule #1: HER2/HER3/NRG1b Heterocomplex in the context of near full-length ...
Supramolecule | Name: HER2/HER3/NRG1b Heterocomplex in the context of near full-length receptors type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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-Supramolecule #2: HER3
Supramolecule | Name: HER3 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Supramolecule #3: HER2-MBP Fusion
Supramolecule | Name: HER2-MBP Fusion / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Supramolecule #4: neuregulin-1
Supramolecule | Name: neuregulin-1 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #2 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Escherichia coli (E. coli) |
-Macromolecule #1: Receptor tyrosine-protein kinase erbB-3
Macromolecule | Name: Receptor tyrosine-protein kinase erbB-3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 117.852719 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MRANDALQVL GLLFSLARGS EVGNSQAVCP GTLNGLSVTG DAENQYQTLY KLYERCEVVM GNLEIVLTGH NADLSFLQWI REVTGYVLV AMNEFSTLPL PNLRVVRGTQ VYDGKFAIFV MLNYNTNSSH ALRQLRLTQL TEILSGGVYI EKNDKLCHMD T IDWRDIVR ...String: MRANDALQVL GLLFSLARGS EVGNSQAVCP GTLNGLSVTG DAENQYQTLY KLYERCEVVM GNLEIVLTGH NADLSFLQWI REVTGYVLV AMNEFSTLPL PNLRVVRGTQ VYDGKFAIFV MLNYNTNSSH ALRQLRLTQL TEILSGGVYI EKNDKLCHMD T IDWRDIVR DRDAEIVVKD NGRSCPPCHE VCKGRCWGPG SEDCQTLTKT ICAPQCNGHC FGPNPNQCCH DECAGGCSGP QD TDCFACR HFNDSGACVP RCPQPLVYNK LTFQLEPNPH TKYQYGGVCV ASCPHNFVVD QTSCVRACPP DKMEVDKNGL KMC EPCGGL CPKACEGTGS GSRFQTVDSS NIDGFVNCTK ILGNLDFLIT GLNGDPWHKI PALDPEKLNV FRTVREITGY LNIQ SWPPH MHNFSVFSNL TTIGGRSLYN RGFSLLIMKN LNVTSLGFRS LKEISAGRIY ISANRQLCYH HSLNWTKVLR GPTEE RLDI KHNRPRRDCV AEGKVCDPLC SSGGCWGPGP GQCLSCRNYS RGGVCVTHCN FLNGEPREFA HEAECFSCHP ECQPME GTA TCNGSGSDTC AQCAHFRDGP HCVSSCPHGV LGAKGPIYKY PDVQNECRPC HENCTQGCKG PELQDCLGQT LVLIGKT HL TMALTVIAGL VVIFMMLGGT FLYWRGRRIQ NKRAMRRYLE RGESIEPLDP SEKANKVLAR IFKETELRKL KVLGSGVF G TVHKGVWIPE GESIKIPVCI KVIEDKSGRQ SFQAVTDHML AIGSLDHAHI VRLLGLCPGS SLQLVTQYLP LGSLLDHVR QHRGALGPRL LLNWGVQIAK GMYYLEEHGM VHRNLAARNV LLKSPSQVQV ADFGVADLLP PDDKQLLYSE AKTPIKWMAL ESIHFGKYT HQSDVWSYGV TVWELMTFGA EPYAGLRLAE VPDLLEKGGR LAQPQICTID VYMVMVKCWM IDENIRPTFK E LANEFTRM ARDPPRYLVI KRESGPGIAP GPEPHGLTNK KLEEVELEPE LDLDLDLEAE EDNGGSLEVL FQGPSSPSAW SH PQFEKGG GSGGGSGGSS AWSHPQFEK |
-Macromolecule #2: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
Macromolecule | Name: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 9.748859 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: GPSHLVKCAE KEKTFCVNGG ECFMVKDLSN PSRYLCKCPN EFTGDRCQNY VMASFYKHLG IEGSGSGSDY KDDDDKAAAL EHHHHHH |
-Macromolecule #3: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-bind...
Macromolecule | Name: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-binding periplasmic protein type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Escherichia coli (E. coli) / Strain: K12 |
Molecular weight | Theoretical: 160.496469 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MELAALCRWG LLLALLPPGA ASTQVCTGTD MKLRLPASPE THLDMLRHLY QGCQVVQGNL ELTYLPTNAS LSFLQDIQEV QGYVLIAHN QVRQVPLQRL RIVRGTQLFE DNYALAVLDN GDPLNNTTPV TGASPGGLRE LQLRSLTEIL KGGVLIQRNP Q LCYQDTIL ...String: MELAALCRWG LLLALLPPGA ASTQVCTGTD MKLRLPASPE THLDMLRHLY QGCQVVQGNL ELTYLPTNAS LSFLQDIQEV QGYVLIAHN QVRQVPLQRL RIVRGTQLFE DNYALAVLDN GDPLNNTTPV TGASPGGLRE LQLRSLTEIL KGGVLIQRNP Q LCYQDTIL WKDIFHKNNQ LALTLIDTNR SRACHPCSPM CKGSRCWGES SEDCQSLTRT VCAGGCARCK GPLPTDCCHE QC AAGCTGP KHSDCLACLH FNHSGICELH CPALVTYNTD TFESMPNPEG RYTFGASCVT ACPYNYLSTD VGSCTLVCPL HNQ EVTAED GTQRCEKCSK PCARVCYGLG MEHLREVRAV TSANIQEFAG CKKIFGSLAF LPESFDGDPA SNTAPLQPEQ LQVF ETLEE ITGYLYISAW PDSLPDLSVF QNLQVIRGRI LHNGAYSLTL QGLGISWLGL RSLRELGSGL ALIHHNTHLC FVHTV PWDQ LFRNPHQALL HTANRPEDEC VGEGLACHQL CARGHCWGPG PTQCVNCSQF LRGQECVEEC RVLQGLPREY VNARHC LPC HPECQPQNGS VTCFGPEADQ CVACAHYKDP PFCVARCPSG VKPDLSYMPI WKFPDEEGAC QPCPINCTHS CVDLDDK GC PAEQRASPLT SIISAVVGIL LVVVLGVVFG ILIKRRQQKI RKYTMRRLLQ ETELVEPLTP SGAMPNQAQM RILKETEL R KVKVLGSGAF GTVYKGIWIP DGENVKIPVA IKVLRENTSP KANKEILDEA YVMAGVDSPY VSRLLGICLT STVQLVTQL MPYGCLLDHV RENRGRLGSQ DLLNWCMQIA KGMSYLEDVR LVHRDLAARN VLVKSPNHVK ITDFGLARLL DIDETEYHAD GGKVPIKWM ALESILRRRF THQSDVWSYG VTVWELMTFG AKPYDGIPAR EIPDLLEKGE RLPQPPICTI DVYMIMVKCW M IDSECRPR FRELVSEFSR MARDPQRFVV IQNEDLGPAS PLDSTFYRSL LEDDDMGDLV DAEEYLVPQQ GGGSLEVLFQ GP SSPSGSS MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQ SGLLAE ITPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQ EPYFT WPLIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAW SNID TSKVNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELA KDP RIAATMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDEALKDAQ TNSSSSGPSS PSAWSHPQFE KGGGSGG GS GGSSAWSHPQ FEK |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 67.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |