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- PDB-7lok: Structure of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 HI... -

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Entry
Database: PDB / ID: 7lok
TitleStructure of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 HIV-1 Env trimer and 17b Fab
Components
  • 17b Fab Heavy Chain
  • 17b Fab Light Chain
  • Envelope Glycoprotein BG505 SOSIP.664 gp41
  • Envelope glycoprotein BG505 SOSIP.664 gp120
  • M48U1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV-1 / fusion / entry / membrane / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope ...positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / identical protein binding / plasma membrane
Similarity search - Function
Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120
Similarity search - Domain/homology
Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
Leiurus quinquestriatus hebraeus (scorpion)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsJette, C.A. / Bjorkman, P.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)2 P50 AI150464 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HIVRAD P01 AI100148 United States
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation.
Authors: Claudia A Jette / Christopher O Barnes / Sharon M Kirk / Bruno Melillo / Amos B Smith / Pamela J Bjorkman /
Abstract: Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host ...Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host receptor CD4, which triggers conformational changes allowing binding to a coreceptor and subsequent membrane fusion. Small molecule or peptide CD4-mimetic drugs mimic CD4's Phe43 interaction with Env by inserting into the conserved Phe43 pocket on Env subunit gp120. Here, we present single-particle cryo-EM structures of CD4-mimetics BNM-III-170 and M48U1 bound to a BG505 native-like Env trimer plus the CD4-induced antibody 17b at 3.7 Å and 3.9 Å resolution, respectively. CD4-mimetic-bound BG505 exhibits canonical CD4-induced conformational changes including trimer opening, formation of the 4-stranded gp120 bridging sheet, displacement of the V1V2 loop, and formation of a compact and elongated gp41 HR1C helical bundle. We conclude that CD4-induced structural changes on both gp120 and gp41 Env subunits are induced by binding to the gp120 Phe43 pocket.
History
DepositionFeb 10, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
C: Envelope glycoprotein BG505 SOSIP.664 gp120
D: Envelope Glycoprotein BG505 SOSIP.664 gp41
A: Envelope glycoprotein BG505 SOSIP.664 gp120
B: Envelope Glycoprotein BG505 SOSIP.664 gp41
J: 17b Fab Light Chain
K: 17b Fab Heavy Chain
L: 17b Fab Light Chain
M: 17b Fab Heavy Chain
G: M48U1
H: M48U1
F: Envelope Glycoprotein BG505 SOSIP.664 gp41
E: Envelope glycoprotein BG505 SOSIP.664 gp120
I: M48U1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)325,00224
Polymers320,49913
Non-polymers4,50211
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 6 molecules CAEDBF

#1: Protein Envelope glycoprotein BG505 SOSIP.664 gp120


Mass: 53864.086 Da / Num. of mol.: 3 / Mutation: BG505 SOSIP.664
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6
#2: Protein Envelope Glycoprotein BG505 SOSIP.664 gp41


Mass: 17146.482 Da / Num. of mol.: 3 / Mutation: BG505 SOSIP.664
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6

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Protein/peptide , 1 types, 3 molecules GHI

#5: Protein/peptide M48U1


Mass: 3056.804 Da / Num. of mol.: 3 / Source method: obtained synthetically
Source: (synth.) Leiurus quinquestriatus hebraeus (scorpion)

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Antibody , 2 types, 4 molecules JLKM

#3: Antibody 17b Fab Light Chain


Mass: 23399.898 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#4: Antibody 17b Fab Heavy Chain


Mass: 25748.771 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)

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Sugars , 4 types, 11 molecules

#6: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c6-d1_d3-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#8: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#9: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
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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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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1Human immunodeficiency virus 1Subtypes of HIVCOMPLEXBG505 SOSIP.664 Env trimer in complex with CD4 mimetic M48U1 and 17b Fab#1-#50MULTIPLE SOURCES
217b antibody FabCOMPLEX#3-#41RECOMBINANT
3M48U1COMPLEXSynthetic peptide, CD4 mimetic#51SYNTHETIC
4BG505 SOSIP.664 EnvCOMPLEX#1-#21RECOMBINANT
Molecular weight
IDEntity assembly-IDExperimental value
11
21NO
31
41NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
32Homo sapiens (human)9606
43Leiurus quinquestriatus hebraeus (scorpion)6884
54Human immunodeficiency virus 111676BG505
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
32Homo sapiens (human)9606HEK293
54Homo sapiens (human)9606HEK293
Details of virus
IDEntity assembly-IDEmptyEnveloped
11YESNO
22
33
44
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris1
2100 mMSodium chlorideNaClSodium chloride1
SpecimenConc.: 1.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295.5 K

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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: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2688

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
7UCSF Chimeramodel fitting
8PHENIX1.18model fitting
10PHENIX1.18model refinement
14RELION3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 263981 / Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-ID
16U0L1
24JZZ1
32NXY1
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00616395
ELECTRON MICROSCOPYf_angle_d1.15422261
ELECTRON MICROSCOPYf_dihedral_angle_d16.2065970
ELECTRON MICROSCOPYf_chiral_restr0.1042587
ELECTRON MICROSCOPYf_plane_restr0.0132791

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