2AEB

Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.29 Å
  • R-Value Free: 0.152 

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This is version 1.6 of the entry. See complete history


Literature

Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in the immune response.

Di Costanzo, L.Sabio, G.Mora, A.Rodriguez, P.C.Ochoa, A.C.Centeno, F.Christianson, D.W.

(2005) Proc Natl Acad Sci U S A 102: 13058-13063

  • DOI: https://doi.org/10.1073/pnas.0504027102
  • Primary Citation of Related Structures:  
    1WVA, 2AEB

  • PubMed Abstract: 

    Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised l-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-A resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions and fully saturated hydrogen bond networks with inhibitor alpha-amino and alpha-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for l-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of l-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.


  • Organizational Affiliation

    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Arginase 1
A, B
322Homo sapiensMutation(s): 0 
EC: 3.5.3.1
UniProt & NIH Common Fund Data Resources
Find proteins for P05089 (Homo sapiens)
Explore P05089 
Go to UniProtKB:  P05089
PHAROS:  P05089
GTEx:  ENSG00000118520 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05089
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
ABH Binding MOAD:  2AEB Kd: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.29 Å
  • R-Value Free: 0.152 
  • Space Group: P 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.422α = 90
b = 91.422β = 90
c = 69.637γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
CNSrefinement
SHELXL-97refinement
HKL-2000data reduction
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-09-06
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2011-07-27
    Changes: Version format compliance
  • Version 1.4: 2013-04-03
    Changes: Other
  • Version 1.5: 2018-03-07
    Changes: Experimental preparation
  • Version 1.6: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description