5VK2

Structural basis for antibody-mediated neutralization of Lassa virus

PDB DOI: https://doi.org/10.2210/pdb5VK2/pdb

Classification: VIRAL PROTEIN/Immune system
Organism(s): Lassa virus Josiah, Homo sapiens
Expression System: Drosophila, Cricetulus griseus
Mutation(s): Yes

Deposited: 2017-04-20 Released: 2017-05-31
Deposition Author(s): Hastie, K.M., Zandonatti, M.A., Kleinfelter, L.M., Rowland, M.L., Rowland, M.M., Chandra, K., Branco, L.M., Robinson, J.E., Garry, R.F., Saphire, E.O.
Funding Organization(s): National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID), National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.20 Å
R-Value Free: 0.231
R-Value Work: 0.189
R-Value Observed: 0.191

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Structural basis for antibody-mediated neutralization of Lassa virus.

Hastie, K.M., Zandonatti, M.A., Kleinfelter, L.M., Heinrich, M.L., Rowland, M.M., Chandran, K., Branco, L.M., Robinson, J.E., Garry, R.F., Saphire, E.O.

(2017) Science 356: 923-928

PubMed: 28572385 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1126/science.aam7260
Primary Citation of Related Structures:
5VK2

PubMed Abstract:
The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health.

Organizational Affiliation

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.

Macromolecule Content

Total Structure Weight: 299.8 kDa
Atom Count: 18,672
Modelled Residue Count: 2,313
Deposited Residue Count: 2,607
Unique protein chains: 4

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Pre-glycoprotein polyprotein GP complex	A, C [auth B], E [auth C]	259	Lassa virus Josiah	Mutation(s): 3 Gene Names: GPC, GP-C
UniProt
Find proteins for P08669 (Lassa virus (strain Mouse/Sierra Leone/Josiah/1976)) Explore P08669 Go to UniProtKB: P08669
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08669
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Pre-glycoprotein polyprotein GP complex	B [auth a], D [auth b], F [auth c]	164	Lassa virus Josiah	Mutation(s): 3 Gene Names: GPC, GP-C
UniProt
Find proteins for P08669 (Lassa virus (strain Mouse/Sierra Leone/Josiah/1976)) Explore P08669 Go to UniProtKB: P08669
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08669
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Fab 37.7H heavy chain	G [auth D], I [auth F], K [auth H]	229	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
Fab 37.7H light chain	H [auth E], J [auth G], L	217	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 5
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	CA [auth Z], M [auth I], Y [auth V]	3		N-Glycosylation	Interactions Focus chain CA [auth Z] Focus chain M [auth I] Focus chain Y [auth V] Interactions & Density Focus chain CA [auth Z] Focus chain M [auth I] Focus chain Y [auth V]
Glycosylation Resources
GlyTouCan: G15407YE GlyCosmos: G15407YE GlyGen: G15407YE

Entity ID: 6
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	AA [auth X], BA [auth Y], EA [auth e], N [auth J], O [auth K], AA [auth X], BA [auth Y], EA [auth e], N [auth J], O [auth K], P [auth M], R [auth O], T [auth Q], U [auth R], V [auth S], Z [auth W]	2		N-Glycosylation	Interactions Focus chain AA [auth X] Focus chain BA [auth Y] Focus chain EA [auth e] Focus chain N [auth J] Focus chain O [auth K] Focus chain P [auth M] Focus chain R [auth O] Focus chain T [auth Q] Focus chain U [auth R] Focus chain V [auth S] Focus chain Z [auth W] Interactions & Density Focus chain AA [auth X] Focus chain BA [auth Y] Focus chain EA [auth e] Focus chain N [auth J] Focus chain O [auth K] Focus chain P [auth M] Focus chain R [auth O] Focus chain T [auth Q] Focus chain U [auth R] Focus chain V [auth S] Focus chain Z [auth W]
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Entity ID: 7
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
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	DA [auth d], Q [auth N], W [auth T]	4		N-Glycosylation	Interactions Focus chain DA [auth d] Focus chain Q [auth N] Focus chain W [auth T] Interactions & Density Focus chain DA [auth d] Focus chain Q [auth N] Focus chain W [auth T]
Glycosylation Resources
GlyTouCan: G81315DD GlyCosmos: G81315DD GlyGen: G81315DD

Entity ID: 8
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	FA [auth f], S [auth P], X [auth U]	3		N-Glycosylation	Interactions Focus chain FA [auth f] Focus chain S [auth P] Focus chain X [auth U] Interactions & Density Focus chain FA [auth f] Focus chain S [auth P] Focus chain X [auth U]
Glycosylation Resources
GlyTouCan: G21290RB GlyCosmos: G21290RB GlyGen: G21290RB

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 GA [auth A] SDF format, chain HA [auth A] SDF format, chain IA [auth A] SDF format, chain JA [auth a] SDF format, chain KA [auth B] SDF format, chain LA [auth B] SDF format, chain MA [auth B] SDF format, chain NA [auth b] SDF format, chain OA [auth C] SDF format, chain PA [auth C] SDF format, chain QA [auth c] MOL2 format, chain GA [auth A] MOL2 format, chain HA [auth A] MOL2 format, chain IA [auth A] MOL2 format, chain JA [auth a] MOL2 format, chain KA [auth B] MOL2 format, chain LA [auth B] MOL2 format, chain MA [auth B] MOL2 format, chain NA [auth b] MOL2 format, chain OA [auth C] MOL2 format, chain PA [auth C] MOL2 format, chain QA [auth c]	GA [auth A] HA [auth A] IA [auth A] JA [auth a] KA [auth B] GA [auth A], HA [auth A], IA [auth A], JA [auth a], KA [auth B], LA [auth B], MA [auth B], NA [auth b], OA [auth C], PA [auth C], QA [auth c]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain GA [auth A] Focus chain HA [auth A] Focus chain IA [auth A] Focus chain JA [auth a] Focus chain KA [auth B] Focus chain LA [auth B] Focus chain MA [auth B] Focus chain NA [auth b] Focus chain OA [auth C] Focus chain PA [auth C] Focus chain QA [auth c] Interactions & Density Focus chain GA [auth A] Focus chain HA [auth A] Focus chain IA [auth A] Focus chain JA [auth a] Focus chain KA [auth B] Focus chain LA [auth B] Focus chain MA [auth B] Focus chain NA [auth b] Focus chain OA [auth C] Focus chain PA [auth C] Focus chain QA [auth c]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.20 Å
R-Value Free: 0.231
R-Value Work: 0.189
R-Value Observed: 0.191
Space Group: P 6₁ 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 152.697	α = 90
b = 152.697	β = 90
c = 456.738	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
Aimless	data scaling
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2017-05-31

Deposition Author(s):

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)	United States	1U19AI109762-01
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)	United States	R21 AI116112
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	United States	T32 GM007491

Revision History (Full details and data files)

Version 1.0: 2017-05-31
Type: Initial release
Version 1.1: 2017-06-14
Changes: Database references
Version 1.2: 2017-09-27
Changes: Author supporting evidence
Version 1.3: 2019-12-11
Changes: Author supporting evidence, Data collection
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2023-10-04
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary