6NM6

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to N6 FR3-03 scFv in Complex with Crystallization Chaperones 3H109L Fab and 35O22 scFv at 3.2 Angstrom

PDB DOI: https://doi.org/10.2210/pdb6NM6/pdb

Classification: IMMUNE SYSTEM
Organism(s): Human immunodeficiency virus 1, Homo sapiens
Expression System: Homo sapiens
Mutation(s): Yes

Deposited: 2019-01-10 Released: 2019-02-27
Deposition Author(s): Lai, Y.-T., Kwong, P.D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.74 Å
R-Value Free: 0.288
R-Value Work: 0.240
R-Value Observed: 0.242

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.1 of the entry. See complete history.

Literature

Improvement of antibody functionality by structure-guided paratope engraftment.

Liu, Q., Lai, Y.T., Zhang, P., Louder, M.K., Pegu, A., Rawi, R., Asokan, M., Chen, X., Shen, C.H., Chuang, G.Y., Yang, E.S., Miao, H., Wang, Y., Fauci, A.S., Kwong, P.D., Mascola, J.R., Lusso, P.

(2019) Nat Commun 10: 721-721

PubMed: 30760721 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/s41467-019-08658-4
Primary Citation of Related Structures:
6NM6, 6NNF, 6NNJ

PubMed Abstract:
Broadly neutralizing antibodies (bNAbs) represent a promising alternative to antiretroviral drugs for HIV-1 prevention and treatment. Selected antibodies to the CD4-binding site bolster envelope trimer binding via quaternary contacts. Here, we rationally engraft a new paratope, i.e., the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bNAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface is delineated by solving the crystal structure of two FR3 loop-chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, chimeric antibodies display lower autoreactivity and prolonged in vivo half-life in huFcRn mice and rhesus macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality for disease prevention and treatment.

Organizational Affiliation

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.

Macromolecule Content

Total Structure Weight: 188.56 kDa
Atom Count: 11,893
Modelled Residue Count: 1,456
Deposited Residue Count: 1,645
Unique protein chains: 8

Macromolecules

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Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Envelope glycoprotein gp41	A [auth B]	153	Human immunodeficiency virus 1	Mutation(s): 2 Gene Names: env
UniProt
Find proteins for Q2N0S6 (Human immunodeficiency virus 1) Explore Q2N0S6 Go to UniProtKB: Q2N0S6
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q2N0S6
Glycosylation
Glycosylation Sites: 3	Glycosylation Focus chain A [auth B]
Sequence Annotations Expand
Reference Sequence

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Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
35O22 scFv heavy chain	B [auth D]	153	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain B [auth D]
Sequence Annotations Expand
Reference Sequence

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Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
35O22 scFv light chain	C [auth E]	130	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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Reference Sequence

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Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
Envelope glycoprotein gp120	D [auth G]	481	Human immunodeficiency virus 1	Mutation(s): 3 Gene Names: env
UniProt
Find proteins for Q2N0S6 (Human immunodeficiency virus 1) Explore Q2N0S6 Go to UniProtKB: Q2N0S6
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q2N0S6
Glycosylation
Glycosylation Sites: 14	Glycosylation Focus chain D [auth G]
Sequence Annotations Expand
Reference Sequence

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Entity ID: 5
Molecule	Chains	Sequence Length	Organism	Details	Image
3H109L Fab heavy chain	E [auth H]	244	Homo sapiens	Mutation(s): 0
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Reference Sequence

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Entity ID: 6
Molecule	Chains	Sequence Length	Organism	Details	Image
3H109L Fab light chain	F [auth L]	217	Homo sapiens	Mutation(s): 0
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Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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Reference Sequence

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Entity ID: 7
Molecule	Chains	Sequence Length	Organism	Details	Image
N6 FR3-03 heavy chain	G [auth U]	145	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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Reference Sequence

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Entity ID: 8
Molecule	Chains	Sequence Length	Organism	Details	Image
N6 FR3-03 light chain	H [auth V]	122	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 9
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
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	I [auth A]	6		N-Glycosylation	Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
Glycosylation Resources
GlyTouCan: G09724ZC GlyCosmos: G09724ZC GlyGen: G09724ZC

Entity ID: 10
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	J [auth C], L [auth I], N [auth K], O [auth M], P [auth N], J [auth C], L [auth I], N [auth K], O [auth M], P [auth N], R [auth P], S [auth Q]	2		N-Glycosylation	Interactions Focus chain J [auth C] Focus chain L [auth I] Focus chain N [auth K] Focus chain O [auth M] Focus chain P [auth N] Focus chain R [auth P] Focus chain S [auth Q] Interactions & Density Focus chain J [auth C] Focus chain L [auth I] Focus chain N [auth K] Focus chain O [auth M] Focus chain P [auth N] Focus chain R [auth P] Focus chain S [auth Q]
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Entity ID: 11
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
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	K [auth F]	5		N-Glycosylation	Interactions Focus chain K [auth F] Interactions & Density Focus chain K [auth F]
Glycosylation Resources
GlyTouCan: G22768VO GlyCosmos: G22768VO GlyGen: G22768VO

Entity ID: 12
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
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	M [auth J]	4		N-Glycosylation	Interactions Focus chain M [auth J] Interactions & Density Focus chain M [auth J]
Glycosylation Resources
GlyTouCan: G22573RC GlyCosmos: G22573RC GlyGen: G22573RC

Entity ID: 13
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[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	Q [auth O]	10		N-Glycosylation	Interactions Focus chain Q [auth O] Interactions & Density Focus chain Q [auth O]
Glycosylation Resources
GlyTouCan: G40702WU GlyCosmos: G40702WU GlyGen: G40702WU

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain T [auth B] SDF format, chain V [auth B] SDF format, chain X [auth G] SDF format, chain Z [auth G] SDF format, chain U [auth B] SDF format, chain W [auth D] SDF format, chain Y [auth G] MOL2 format, chain T [auth B] MOL2 format, chain V [auth B] MOL2 format, chain X [auth G] MOL2 format, chain Z [auth G] MOL2 format, chain U [auth B] MOL2 format, chain W [auth D] MOL2 format, chain Y [auth G] mmCIF format, chain T [auth B] mmCIF format, chain V [auth B] mmCIF format, chain X [auth G] mmCIF format, chain Z [auth G] mmCIF format, chain U [auth B] mmCIF format, chain W [auth D] mmCIF format, chain Y [auth G]	T [auth B] U [auth B] V [auth B] W [auth D] X [auth G] T [auth B], U [auth B], V [auth B], W [auth D], X [auth G], Y [auth G], Z [auth G]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth D] Focus chain X [auth G] Focus chain Y [auth G] Focus chain Z [auth G] Interactions & Density Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth D] Focus chain X [auth G] Focus chain Y [auth G] Focus chain Z [auth G]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.74 Å
R-Value Free: 0.288
R-Value Work: 0.240
R-Value Observed: 0.242
Space Group: P 6₃

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 128.24	α = 90
b = 128.24	β = 90
c = 315.77	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-2000	data reduction
SCALEPACK	data scaling
PDB_EXTRACT	data extraction
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-02-27

Deposition Author(s):

Lai, Y.-T.

Kwong, P.D.

Revision History (Full details and data files)

Version 1.0: 2019-02-27
Type: Initial release
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2024-11-13
Changes: Data collection, Database references, Derived calculations, Structure summary

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.

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Help and Resources

6NM6

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to N6 FR3-03 scFv in Complex with Crystallization Chaperones 3H109L Fab and 35O22 scFv at 3.2 Angstrom

Improvement of antibody functionality by structure-guided paratope engraftment.

Entity ID: 1

UniProt

Entity Groups

Glycosylation

Sequence Annotations

Entity ID: 2

Entity Groups

Glycosylation

Sequence Annotations

Entity ID: 3

Entity Groups

Sequence Annotations

Entity ID: 4

UniProt

Entity Groups

Glycosylation

Sequence Annotations

Entity ID: 5

Entity Groups

Sequence Annotations

Entity ID: 6

Entity Groups

Sequence Annotations

Entity ID: 7

Entity Groups

Sequence Annotations

Entity ID: 8

Entity Groups

Sequence Annotations

Entity ID: 9

Glycosylation Resources

Entity ID: 10

Glycosylation Resources

Entity ID: 11

Glycosylation Resources

Entity ID: 12

Glycosylation Resources

Entity ID: 13

Glycosylation Resources

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)