8KHU

Hepatitis B virus core protein Y132A mutant in complex with THPP derivatives 48

PDB DOI: https://doi.org/10.2210/pdb8KHU/pdb

Classification: VIRAL PROTEIN
Organism(s): Hepatitis B virus adw/991
Expression System: Escherichia coli 'BL21-Gold(DE3)pLysS AG
Mutation(s): Yes

Deposited: 2023-08-22 Released: 2023-10-25
Deposition Author(s): Zhou, Z., Xu, Z.H.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.213
R-Value Work: 0.179
R-Value Observed: 0.180

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus.

Kou, B., Zhang, Z., Han, X., Zhou, Z., Xu, Z., Zhou, X., Shen, F., Zhou, Y., Tian, X., Yang, G., Young, J.A.T., Qiu, H., Ottaviani, G., Mayweg, A., Zhu, W., Shen, H.C., Liu, H., Hu, T.

(2023) J Med Chem 66: 14116-14132

PubMed: 37801325 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.3c01145
Primary Citation of Related Structures:
8KHU

PubMed Abstract:
Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.

Organizational Affiliation

China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China.

Macromolecule Content

Total Structure Weight: 125.37 kDa
Atom Count: 7,565
Modelled Residue Count: 882
Deposited Residue Count: 1,085
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Capsid protein	A, B, C, D, E A, B, C, D, E, F, G	155	Hepatitis B virus adw/991	Mutation(s): 1
UniProt
Find proteins for P03147 (Hepatitis B virus genotype D subtype adw (isolate United Kingdom/adyw/1979)) Explore P03147 Go to UniProtKB: P03147
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P03147
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
VX0 (Subject of Investigation/LOI) Query on VX0 Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain L [auth B] SDF format, chain N [auth C] SDF format, chain P [auth D] SDF format, chain S [auth E] SDF format, chain T [auth F] MOL2 format, chain J [auth A] MOL2 format, chain L [auth B] MOL2 format, chain N [auth C] MOL2 format, chain P [auth D] MOL2 format, chain S [auth E] MOL2 format, chain T [auth F] mmCIF format, chain J [auth A] mmCIF format, chain L [auth B] mmCIF format, chain N [auth C] mmCIF format, chain P [auth D] mmCIF format, chain S [auth E] mmCIF format, chain T [auth F]	J [auth A] L [auth B] N [auth C] P [auth D] S [auth E] J [auth A], L [auth B], N [auth C], P [auth D], S [auth E], T [auth F]	(6~{S},7~{R})-6,7-dimethyl-3-(2-oxidanylidenepyrrolidin-1-yl)-~{N}-[3,4,5-tris(fluoranyl)phenyl]-6,7-dihydro-4~{H}-pyrazolo[1,5-a]pyrazine-5-carboxamide C₁₉ H₂₀ F₃ N₅ O₂ SUOFMBIUXLAFSN-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain L [auth B] Focus chain N [auth C] Focus chain P [auth D] Focus chain S [auth E] Focus chain T [auth F] Interactions & Density Focus chain J [auth A] Focus chain L [auth B] Focus chain N [auth C] Focus chain P [auth D] Focus chain S [auth E] Focus chain T [auth F]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain U [auth F] MOL2 format, chain U [auth F] mmCIF format, chain U [auth F]	U [auth F]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain U [auth F] Interactions & Density Focus chain U [auth F]
IPA Query on IPA Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain K [auth B] SDF format, chain M [auth C] SDF format, chain O [auth D] SDF format, chain Q [auth E] SDF format, chain R [auth E] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain K [auth B] MOL2 format, chain M [auth C] MOL2 format, chain O [auth D] MOL2 format, chain Q [auth E] MOL2 format, chain R [auth E] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain K [auth B] mmCIF format, chain M [auth C] mmCIF format, chain O [auth D] mmCIF format, chain Q [auth E] mmCIF format, chain R [auth E]	H [auth A] I [auth A] K [auth B] M [auth C] O [auth D] H [auth A], I [auth A], K [auth B], M [auth C], O [auth D], Q [auth E], R [auth E]	ISOPROPYL ALCOHOL C₃ H₈ O KFZMGEQAYNKOFK-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain I [auth A] Focus chain K [auth B] Focus chain M [auth C] Focus chain O [auth D] Focus chain Q [auth E] Focus chain R [auth E] Interactions & Density Focus chain H [auth A] Focus chain I [auth A] Focus chain K [auth B] Focus chain M [auth C] Focus chain O [auth D] Focus chain Q [auth E] Focus chain R [auth E]