4IE2

Crystal structure of human Arginase-2 complexed with inhibitor 1h


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.21 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors.

Golebiowski, A.Paul Beckett, R.Van Zandt, M.Ji, M.K.Whitehouse, D.Ryder, T.R.Jagdmann, E.Andreoli, M.Mazur, A.Padmanilayam, M.Cousido-Siah, A.Mitschler, A.Ruiz, F.X.Podjarny, A.Schroeter, H.

(2013) Bioorg Med Chem Lett 23: 2027-2030

  • DOI: https://doi.org/10.1016/j.bmcl.2013.02.024
  • Primary Citation of Related Structures:  
    4IE1, 4IE2, 4IE3

  • PubMed Abstract: 

    Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.


  • Organizational Affiliation

    Institutes for Pharmaceutical Discovery, 23 Business Park Drive, Branford, CT, USA. golebiowski.a@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Arginase-2, mitochondrial
A, B, C
306Homo sapiensMutation(s): 0 
Gene Names: ARG2
EC: 3.5.3.1
UniProt & NIH Common Fund Data Resources
Find proteins for P78540 (Homo sapiens)
Explore P78540 
Go to UniProtKB:  P78540
PHAROS:  P78540
GTEx:  ENSG00000081181 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP78540
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1EC
Query on 1EC

Download Ideal Coordinates CCD File 
H [auth A],
O [auth B],
T [auth C]
[(5R)-5-amino-5-carboxy-8-hydroxyoctyl](trihydroxy)borate(1-)
C9 H21 B N O6
NLSMSWJRKXBPCL-SECBINFHSA-N
BEN
Query on BEN

Download Ideal Coordinates CCD File 
F [auth A],
L [auth B],
S [auth C]
BENZAMIDINE
C7 H8 N2
PXXJHWLDUBFPOL-UHFFFAOYSA-N
BME
Query on BME

Download Ideal Coordinates CCD File 
G [auth A]
I [auth A]
M [auth B]
N [auth B]
P [auth B]
G [auth A],
I [auth A],
M [auth B],
N [auth B],
P [auth B],
U [auth C]
BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
J [auth B]
K [auth B]
Q [auth C]
D [auth A],
E [auth A],
J [auth B],
K [auth B],
Q [auth C],
R [auth C]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1EC Binding MOAD:  4IE2 IC50: 4500 (nM) from 1 assay(s)
PDBBind:  4IE2 IC50: 4500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.21 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.170 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 128.094α = 90
b = 128.094β = 90
c = 159.085γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-20
    Type: Initial release
  • Version 1.1: 2013-04-03
    Changes: Database references
  • Version 1.2: 2013-12-18
    Changes: Structure summary
  • Version 1.3: 2017-11-15
    Changes: Refinement description
  • Version 1.4: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description