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Structure paper

TitlepH-induced conformational changes and inhibition of the Lassa virus spike complex.
Journal, issue, pagesCell Host Microbe, Vol. 33, Issue 9, Page 1577-11588.e7, Year 2025
Publish dateSep 10, 2025
AuthorsMichael Katz / Hadas Cohen-Dvashi / Sarah Borni / John Ruedas / Greg Henkel / Ken McCormack / Ron Diskin /
PubMed AbstractLassa virus (LASV) is a devastating human pathogen with no vaccines and limited therapeutics. The LASV class-I spike complex engages target cells via binding its primary host receptor, matriglycan, ...Lassa virus (LASV) is a devastating human pathogen with no vaccines and limited therapeutics. The LASV class-I spike complex engages target cells via binding its primary host receptor, matriglycan, followed by macropinocytosis and binding of its secondary receptor, lysosomal-associated membrane protein 1 (LAMP1), to trigger virus fusion. This process occurs across multiple pH-dependent steps, but the molecular events remain largely unknown. Through high-resolution structures, we study the pH-induced conformational changes of the spike preceding membrane fusion. We reveal pH-sensitive metal coordination sites that control the integrity of the spike's native state, elucidate a reorganization of the spike's transmembrane region, and provide a mechanism for dissociation from its primary receptor. Using the entry inhibitor ARN-75039, we validate our findings and establish the molecular basis for the binding and function of this investigational drug. These data define the molecular basis for the cell entry of LASV and will promote efforts in combating this virus and potentially related viral pathogens.
External linksCell Host Microbe / PubMed:40897176
MethodsEM (single particle)
Resolution1.9 - 3.3 Å
Structure data

48275

9mhe

EMDB-48275, PDB-9mhe:
Native tagless Lassa virus spike complex bound to ARN-75039 at pH 8.0
Method: EM (single particle) / Resolution: 2.01 Å

48303

9miv

EMDB-48303, PDB-9miv:
Native tagless Lassa virus spike complex pH 6.0
Method: EM (single particle) / Resolution: 2.02 Å

48305

9miy

EMDB-48305, PDB-9miy:
Focused reconstruction of the transmembrane region of the Lassa virus spike complex
Method: EM (single particle) / Resolution: 2.72 Å

48306

9mj1

EMDB-48306, PDB-9mj1:
Native tagless Lassa virus spike complex bound at pH 8.0
Method: EM (single particle) / Resolution: 1.9 Å

48307

9mj2

EMDB-48307, PDB-9mj2:
Flag-tag Lassa virus spike complex at pH 6.0
Method: EM (single particle) / Resolution: 2.58 Å

48308

9r8u

EMDB-48308: Map of LASV spike complex after exposure to pH 5.0 and re-equilibration to pH 8.0
PDB-9r8u: Flag-tag LASV spike acidified to pH 5.0 and re-equilibrated to pH 8.0
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-48309: LASV spike complex bound to ARN-75039 at pH 6.0
Method: EM (single particle) / Resolution: 3.22 Å

EMDB-53842: LASV tagless in complex with 12.1F Fab reconstructed at C1
Method: EM (single particle) / Resolution: 1.99 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-UNX:
Unknown entry

PDB-1bk9:
PHOSPHOLIPASE A2 MODIFIED BY PBPB

ChemComp-HOH:
WATER

Source
  • lassa virus josiah
  • homo sapiens (human)
KeywordsVIRAL PROTEIN / Spike complex

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