7VE0

Crystal Structure of Ritonavir bound Plasmepsin II (PMII) from Plasmodium falciparum

PDB DOI: https://doi.org/10.2210/pdb7VE0/pdb

Classification: HYDROLASE
Organism(s): Plasmodium falciparum 3D7
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2021-09-07 Released: 2023-02-01
Deposition Author(s): Mishra, V., Rathore, I., Bhaumik, P.
Funding Organization(s): Department of Biotechnology (DBT, India)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.261
R-Value Work: 0.222
R-Value Observed: 0.224

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery.

Mishra, V., Deshmukh, A., Rathore, I., Chakraborty, S., Patankar, S., Gustchina, A., Wlodawer, A., Yada, R.Y., Bhaumik, P.

(2024) Curr Res Struct Biol 7: 100128-100128

PubMed: 38304146 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1016/j.crstbi.2024.100128
Primary Citation of Related Structures:
7VE0, 7VE2

PubMed Abstract:
Plasmodium species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by Plasmodium parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating Plasmodium pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of P. falciparum. Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII via multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of P. falciparum PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs.

Organizational Affiliation

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India.

Macromolecule Content

Total Structure Weight: 85.02 kDa
Atom Count: 6,239
Modelled Residue Count: 655
Deposited Residue Count: 662
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Plasmepsin II	A, B	331	Plasmodium falciparum 3D7	Mutation(s): 0 Gene Names: PF3D7_1408000 EC: 3.4.23.39
UniProt
Find proteins for Q8I6V3 (Plasmodium falciparum (isolate 3D7)) Explore Q8I6V3 Go to UniProtKB: Q8I6V3
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q8I6V3
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
RIT (Subject of Investigation/LOI) Query on RIT Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain L [auth B] MOL2 format, chain C [auth A] MOL2 format, chain L [auth B] mmCIF format, chain C [auth A] mmCIF format, chain L [auth B]	C [auth A], L [auth B]	RITONAVIR C₃₇ H₄₈ N₆ O₅ S₂ NCDNCNXCDXHOMX-XGKFQTDJSA-N		Interactions Focus chain C [auth A] Focus chain L [auth B] Interactions & Density Focus chain C [auth A] Focus chain L [auth B]
CPS Query on CPS 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] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] H [auth A] D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], M [auth B], N [auth B], O [auth B], P [auth B], Q [auth B], R [auth B], S [auth B], T [auth B]	3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE C₃₂ H₅₈ N₂ O₇ S UMCMPZBLKLEWAF-BCTGSCMUSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain U [auth B] MOL2 format, chain K [auth A] MOL2 format, chain U [auth B] mmCIF format, chain K [auth A] mmCIF format, chain U [auth B]	K [auth A], U [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Focus chain U [auth B] Interactions & Density Focus chain K [auth A] Focus chain U [auth B]

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 2
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_001001 (RIT) Query on PRD_001001	C [auth A], L [auth B]	RITONAVIR	Peptide-like / Inhibitor		Interactions Focus chain C [auth A] Focus chain L [auth B] Interactions & Density Focus chain C [auth A] Focus chain L [auth B]