RCSB PDB - 5YIE: Crystal Structure of KNI-10742 bound Plasmepsin II (PMII) from Plasmodium falciparum

 5YIE

Crystal Structure of KNI-10742 bound Plasmepsin II (PMII) from Plasmodium falciparum


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8VFClick on this verticalbar to view detailsBest fitted CPSClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins - biochemical and structural insights.

Mishra, V.Rathore, I.Arekar, A.Sthanam, L.K.Xiao, H.Kiso, Y.Sen, S.Patankar, S.Gustchina, A.Hidaka, K.Wlodawer, A.Yada, R.Y.Bhaumik, P.

(2018) FEBS J 285: 3077-3096

  • DOI: https://doi.org/10.1111/febs.14598
  • Primary Citation of Related Structures:  
    5YIA, 5YIB, 5YIC, 5YID, 5YIE

  • PubMed Abstract: 

    Malaria is a deadly disease killing worldwide hundreds of thousands people each year and the responsible parasite has acquired resistance to the available drug combinations. The four vacuolar plasmepsins (PMs) in Plasmodium falciparum involved in hemoglobin (Hb) catabolism represent promising targets to combat drug resistance. High antimalarial activities can be achieved by developing a single drug that would simultaneously target all the vacuolar PMs. We have demonstrated for the first time the use of soluble recombinant plasmepsin II (PMII) for structure-guided drug discovery with KNI inhibitors. Compounds used in this study (KNI-10742, 10743, 10395, 10333, and 10343) exhibit nanomolar inhibition against PMII and are also effective in blocking the activities of PMI and PMIV with the low nanomolar K i values. The high-resolution crystal structures of PMII-KNI inhibitor complexes reveal interesting features modulating their differential potency. Important individual characteristics of the inhibitors and their importance for potency have been established. The alkylamino analog, KNI-10743, shows intrinsic flexibility at the P2 position that potentiates its interactions with Asp132, Leu133, and Ser134. The phenylacetyl tripeptides, KNI-10333 and KNI-10343, accommodate different ρ-substituents at the P3 phenylacetyl ring that determine the orientation of the ring, thus creating novel hydrogen-bonding contacts. KNI-10743 and KNI-10333 possess significant antimalarial activity, block Hb degradation inside the food vacuole, and show no cytotoxicity on human cells; thus, they can be considered as promising candidates for further optimization. Based on our structural data, novel KNI derivatives with improved antimalarial activity could be designed for potential clinical use. DATABASE: Structural data are available in the PDB under the accession numbers 5YIE, 5YIB, 5YID, 5YIC, and 5YIA.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Plasmepsin II327Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF14_0077PF3D7_1408000
EC: 3.4.23.39
UniProt
Find proteins for Q8I6V3 (Plasmodium falciparum (isolate 3D7))
Explore Q8I6V3 
Go to UniProtKB:  Q8I6V3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8I6V3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8VF
Query on 8VF

Download Ideal Coordinates CCD File 
D [auth A](4R)-3-[(2S,3S)-3-[2-[4-[2-azanylethyl(ethyl)amino]-2,6-dimethyl-phenoxy]ethanoylamino]-2-oxidanyl-4-phenyl-butanoyl]-5,5-dimethyl-N-[(1S,2R)-2-oxidanyl-2,3-dihydro-1H-inden-1-yl]-1,3-thiazolidine-4-carboxamide
C39 H51 N5 O6 S
QVEVEYWLPLMZQY-SQKWSBCUSA-N
CPS
Query on CPS

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE
C32 H58 N2 O7 S
UMCMPZBLKLEWAF-BCTGSCMUSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
E [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8VF BindingDB:  5YIE Ki: 0.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 
  • Space Group: I 4
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.6α = 90
b = 106.6β = 90
c = 72.2γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8VFClick on this verticalbar to view detailsBest fitted CPSClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Department of Biotechnology, Government of IndiaIndiaRamalingaswami Re-entry Fellowship

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-11
    Type: Initial release
  • Version 1.1: 2018-07-18
    Changes: Data collection, Database references
  • Version 1.2: 2019-05-29
    Changes: Data collection, Database references
  • Version 1.3: 2024-11-13
    Changes: Data collection, Database references, Structure summary