2H31

Crystal structure of human PAICS, a bifunctional carboxylase and synthetase in purine biosynthesis


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.241 
  • R-Value Observed: 0.245 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis.

Li, S.X.Tong, Y.P.Xie, X.C.Wang, Q.H.Zhou, H.N.Han, Y.Zhang, Z.Y.Gao, W.Li, S.G.Zhang, X.C.Bi, R.C.

(2007) J Mol Biol 366: 1603-1614

  • DOI: https://doi.org/10.1016/j.jmb.2006.12.027
  • Primary Citation of Related Structures:  
    2H31

  • PubMed Abstract: 

    Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities. It becomes an attractive target for rational anticancer drug design, since rapidly dividing cancer cells rely heavily on the purine de novo pathway for synthesis of adenine and guanine, whereas normal cells favor the salvage pathway. Here, we report the crystal structure of human PAICS, the first in the entire PAICS family, at 2.8 A resolution. It revealed that eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains. Based on structural comparison and functional complementation analyses, the active sites of SAICARs and AIRc were identified, including a putative substrate CO(2)-binding site. Furthermore, four symmetry-related, separate tunnel systems in the PAICS octamer were found that connect the active sites of AIRc and SAICARs. This study illustrated the octameric nature of the bifunctional enzyme. Each carboxylase active site is formed by structural elements from three AIRc domains, demonstrating that the octamer structure is essential for the carboxylation activity. Furthermore, the existence of the tunnel system implies a mechanism of intermediate channeling and suggests that the quaternary structure arrangement is crucial for effectively executing the sequential reactions. In addition, this study provides essential structural information for designing PAICS-specific inhibitors for use in cancer chemotherapy.


  • Organizational Affiliation

    Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Multifunctional protein ADE2425Homo sapiensMutation(s): 6 
Gene Names: PAICSADE2AIRCPAIS
EC: 6.3.2.6 (PDB Primary Data), 4.1.1.21 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P22234 (Homo sapiens)
Explore P22234 
Go to UniProtKB:  P22234
PHAROS:  P22234
GTEx:  ENSG00000128050 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22234
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CO2
Query on CO2

Download Ideal Coordinates CCD File 
B [auth A]CARBON DIOXIDE
C O2
CURLTUGMZLYLDI-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MSE
Query on MSE
A
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.241 
  • R-Value Observed: 0.245 
  • Space Group: P 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 133.666α = 90
b = 133.666β = 90
c = 60.618γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
HKL-2000data reduction
SOLVEphasing
CNSrefinement
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-01-30
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance