3Q43

X-ray crystal structure of PfA-M1 bound to bestatin derivative 15


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the s1 pocket of the essential malaria m1 metalloaminopeptidase.

Velmourougane, G.Harbut, M.B.Dalal, S.McGowan, S.Oellig, C.A.Meinhardt, N.Whisstock, J.C.Klemba, M.Greenbaum, D.C.

(2011) J Med Chem 54: 1655-1666

  • DOI: https://doi.org/10.1021/jm101227t
  • Primary Citation of Related Structures:  
    3Q43, 3Q44

  • PubMed Abstract: 

    The malarial PfA-M1 metallo-aminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-d-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the α-hydroxy-β-amino acid (P1) or the adjacent natural α-amino acid (P1'). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBzl) 16 at the P1 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PfA-M1 pocket that interacts with the P1 side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria.


  • Organizational Affiliation

    Department of Pharmacology, University of Pennsylvania, 433 South University Avenue, 304G Lynch Laboratories, Philadelphia, Pennsylvania 19104-6018, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
M1 family aminopeptidase891Plasmodium falciparum FcB1/ColumbiaMutation(s): 7 
EC: 3.4.11
UniProt
Find proteins for O96935 (Plasmodium falciparum (isolate 3D7))
Explore O96935 
Go to UniProtKB:  O96935
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96935
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
D66
Query on D66

Download Ideal Coordinates CCD File 
K [auth A]N-[(2S,3R)-3-amino-2-hydroxy-4-(4-methoxyphenyl)butanoyl]-L-leucine
C17 H26 N2 O5
CIXFVWODUHVKQG-ILXRZTDVSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
G [auth A],
I [auth A],
J [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
F [auth A],
H [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
D66 BindingDB:  3Q43 Ki: 43 (nM) from 1 assay(s)
Binding MOAD:  3Q43 Ki: 43 (nM) from 1 assay(s)
PDBBind:  3Q43 Ki: 43 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.772α = 90
b = 108.814β = 90
c = 118.683γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-16
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description