6NAE

Crystal Structure of Ebola zaire GP protein with bound ARN0074898

PDB DOI: https://doi.org/10.2210/pdb6NAE/pdb

Classification: VIRAL PROTEIN
Organism(s): Ebola virus - Mayinga, Zaire, 1976
Expression System: Homo sapiens
Mutation(s): Yes

Deposited: 2018-12-05 Released: 2019-12-11
Deposition Author(s): Seattle Structural Genomics Center for Infectious Disease (SSGCID)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.75 Å
R-Value Free: 0.240
R-Value Work: 0.193
R-Value Observed: 0.197

Starting Model: experimental
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Ligand Structure Quality Assessment

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

Literature

Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors.

Plewe, M.B., Sokolova, N.V., Gantla, V.R., Brown, E.R., Naik, S., Fetsko, A., Lorimer, D.D., Dranow, D.M., Smutney, H., Bullen, J., Sidhu, R., Master, A., Wang, J., Kallel, E.A., Zhang, L., Kalveram, B., Freiberg, A.N., Henkel, G., McCormack, K.

(2020) ACS Med Chem Lett 11: 1160-1167

PubMed: 32550996 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.0c00025
Primary Citation of Related Structures:
6NAE

PubMed Abstract:
We identified and explored the structure-activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC ₅₀ values) of ∼10-15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC ₅₀ activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.

Organizational Affiliation

Arisan Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, California 92121, United States.

Macromolecule Content

Total Structure Weight: 57.85 kDa
Atom Count: 2,972
Modelled Residue Count: 355
Deposited Residue Count: 498
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Envelope glycoprotein,Envelope glycoprotein,Envelope glycoprotein	A	330	Ebola virus - Mayinga, Zaire, 1976	Mutation(s): 1 Gene Names: GP
UniProt
Find proteins for Q05320 (Zaire ebolavirus (strain Mayinga-76)) Explore Q05320 Go to UniProtKB: Q05320
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q05320
Glycosylation
Glycosylation Sites: 4	Glycosylation Focus chain A
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Envelope glycoprotein	B	168	Ebola virus - Mayinga, Zaire, 1976	Mutation(s): 1 Gene Names: GP
UniProt
Find proteins for Q05320 (Zaire ebolavirus (strain Mayinga-76)) Explore Q05320 Go to UniProtKB: Q05320
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q05320
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain B
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 3
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	C	5		N-Glycosylation	Interactions Focus chain C Interactions & Density Focus chain C
Glycosylation Resources
GlyTouCan: G22768VO GlyCosmos: G22768VO GlyGen: G22768VO

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
KHG Query on KHG Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	(1S,3R,5R,7S)-N-(trans-4-aminocyclohexyl)-3-methyl-5-phenyltricyclo[3.3.1.1~3,7~]decane-1-carboxamide C₂₄ H₃₄ N₂ O TZNRCHUCVIMHIH-UCWUHLBISA-N		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A]	D [auth A], E [auth A], F [auth A], G [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain L [auth A] SDF format, chain M [auth B] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth B] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth B]	H [auth A], I [auth A], J [auth A], L [auth A], M [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain L [auth A] Focus chain M [auth B] Interactions & Density Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain L [auth A] Focus chain M [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.75 Å
R-Value Free: 0.240
R-Value Work: 0.193
R-Value Observed: 0.197
Space Group: H 3 2
Diffraction Data: https://doi.org/10.18430/m36nae

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 113.25	α = 90
b = 113.25	β = 90
c = 307.21	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
XSCALE	data scaling
PHASER	phasing
PDB_EXTRACT	data extraction

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-12-11

Deposition Author(s):

Seattle Structural Genomics Center for Infectious Disease (SSGCID)

Revision History (Full details and data files)

Version 1.0: 2019-12-11
Type: Initial release
Version 1.1: 2019-12-25
Changes: Database references
Version 1.2: 2020-07-01
Changes: Data collection, Database references
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2023-10-11
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary