4I06

Crystal structure of human Arginase-2 complexed with inhibitor 14


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury.

Van Zandt, M.C.Whitehouse, D.L.Golebiowski, A.Ji, M.K.Zhang, M.Beckett, R.P.Jagdmann, G.E.Ryder, T.R.Sheeler, R.Andreoli, M.Conway, B.Mahboubi, K.D'Angelo, G.Mitschler, A.Cousido-Siah, A.Ruiz, F.X.Howard, E.I.Podjarny, A.D.Schroeter, H.

(2013) J Med Chem 56: 2568-2580

  • DOI: https://doi.org/10.1021/jm400014c
  • Primary Citation of Related Structures:  
    4HWW, 4HXQ, 4HZE, 4I06

  • PubMed Abstract: 

    Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.


  • Organizational Affiliation

    Institutes for Pharmaceutical Discovery , LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA. mvzandt@snet.net


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
X8A
Query on X8A

Download Ideal Coordinates CCD File 
I [auth A],
O [auth B],
U [auth C]
[(5R)-5-carboxy-5-(methylamino)-7-(piperidin-1-yl)heptyl](trihydroxy)borate(1-)
C14 H30 B N2 O5
XUSDRKPOXSYXRQ-CQSZACIVSA-N
BEN
Query on BEN

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

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
M [auth B]
N [auth B]
S [auth C]
G [auth A],
H [auth A],
M [auth B],
N [auth B],
S [auth C],
T [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]
P [auth C]
D [auth A],
E [auth A],
J [auth B],
K [auth B],
P [auth C],
Q [auth C]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
X8A Binding MOAD:  4I06 IC50: 67 (nM) from 1 assay(s)
PDBBind:  4I06 IC50: 67 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.805α = 90
b = 127.805β = 90
c = 159.094γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing

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: 2013-04-10
    Changes: Database references
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description