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- PDB-7v61: ACE2 -Targeting Monoclonal Antibody as Potent and Broad-Spectrum ... -

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Basic information

Entry
Database: PDB / ID: 7v61
TitleACE2 -Targeting Monoclonal Antibody as Potent and Broad-Spectrum Coronavirus Blocker
Components
  • (3E8) x 2
  • Angiotensin-converting enzyme 2
  • Sodium-dependent neutral amino acid transporter B(0)AT1
KeywordsMEMBRANE PROTEIN / ACE2-B0AT1 complex
Function / homology
Function and homology information


Defective SLC6A19 causes Hartnup disorder (HND) / Defective SLC6A19 causes Hartnup disorder (HND) / neutral amino acid transport / amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / symporter activity / Na+/Cl- dependent neurotransmitter transporters / amino acid transport / positive regulation of amino acid transport ...Defective SLC6A19 causes Hartnup disorder (HND) / Defective SLC6A19 causes Hartnup disorder (HND) / neutral amino acid transport / amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / symporter activity / Na+/Cl- dependent neurotransmitter transporters / amino acid transport / positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / angiotensin-mediated drinking behavior / regulation of systemic arterial blood pressure by renin-angiotensin / tryptophan transport / positive regulation of gap junction assembly / regulation of cardiac conduction / regulation of vasoconstriction / peptidyl-dipeptidase activity / maternal process involved in female pregnancy / sodium ion transmembrane transport / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / negative regulation of signaling receptor activity / carboxypeptidase activity / Attachment and Entry / positive regulation of cardiac muscle contraction / viral life cycle / regulation of cytokine production / blood vessel diameter maintenance / response to nutrient / negative regulation of smooth muscle cell proliferation / brush border membrane / regulation of transmembrane transporter activity / cilium / negative regulation of ERK1 and ERK2 cascade / metallopeptidase activity / positive regulation of reactive oxygen species metabolic process / endocytic vesicle membrane / virus receptor activity / regulation of cell population proliferation / regulation of inflammatory response / endopeptidase activity / Potential therapeutics for SARS / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / membrane fusion / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / receptor-mediated virion attachment to host cell / symbiont entry into host cell / membrane raft / apical plasma membrane / endoplasmic reticulum lumen / cell surface / extracellular space / extracellular exosome / zinc ion binding / extracellular region / identical protein binding / membrane / plasma membrane
Similarity search - Function
Neutral amino acid SLC6 transporter / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile. / Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A ...Neutral amino acid SLC6 transporter / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile. / Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Sodium-dependent neutral amino acid transporter B(0)AT1 / Angiotensin-converting enzyme 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Severe acute respiratory syndrome coronavirus 2
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYan, R.H. / Zhang, Y.Y. / Li, Y.N. / Zhou, Q.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31971123 China
National Natural Science Foundation of China (NSFC)81920108015 China
National Natural Science Foundation of China (NSFC)31930059 China
Citation
Journal: Signal Transduct Target Ther / Year: 2021
Title: ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker.
Authors: Yuning Chen / Ya-Nan Zhang / Renhong Yan / Guifeng Wang / Yuanyuan Zhang / Zhe-Rui Zhang / Yaning Li / Jianxia Ou / Wendi Chu / Zhijuan Liang / Yongmei Wang / Yi-Li Chen / Ganjun Chen / Qi ...Authors: Yuning Chen / Ya-Nan Zhang / Renhong Yan / Guifeng Wang / Yuanyuan Zhang / Zhe-Rui Zhang / Yaning Li / Jianxia Ou / Wendi Chu / Zhijuan Liang / Yongmei Wang / Yi-Li Chen / Ganjun Chen / Qi Wang / Qiang Zhou / Bo Zhang / Chunhe Wang /
Abstract: The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme ...The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.
#1: Journal: Science / Year: 2020
Title: Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.
Authors: Renhong Yan / Yuanyuan Zhang / Yaning Li / Lu Xia / Yingying Guo / Qiang Zhou /
Abstract: Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious ...Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter BAT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-BAT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.
History
DepositionAug 18, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 22, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium-dependent neutral amino acid transporter B(0)AT1
B: Angiotensin-converting enzyme 2
H: 3E8
K: 3E8
C: Sodium-dependent neutral amino acid transporter B(0)AT1
D: Angiotensin-converting enzyme 2
I: 3E8
M: 3E8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)489,75434
Polymers481,4698
Non-polymers8,28526
Water724
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area26730 Å2
ΔGint-35 kcal/mol
Surface area159640 Å2

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein Sodium-dependent neutral amino acid transporter B(0)AT1 / Solute carrier family 6 member 19 / System B(0) neutral amino acid transporter AT1


Mass: 73289.359 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A19, B0AT1 / Production host: Homo sapiens (human) / References: UniProt: Q695T7
#2: Protein Angiotensin-converting enzyme 2 / ACE-related carboxypeptidase / Angiotensin-converting enzyme homolog / ACEH / Metalloprotease MPROT15


Mass: 93971.266 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2, UNQ868/PRO1885 / Production host: Homo sapiens (human)
References: UniProt: Q9BYF1, angiotensin-converting enzyme 2, Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases

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Antibody , 2 types, 4 molecules HIKM

#3: Antibody 3E8


Mass: 49966.980 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Severe acute respiratory syndrome coronavirus 2
#4: Antibody 3E8


Mass: 23507.031 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Severe acute respiratory syndrome coronavirus 2

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Sugars , 2 types, 24 molecules

#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 6 molecules

#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

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: ACE2-B0AT1 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: RELION / Version: 3.0.6 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101662 / Symmetry type: POINT

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