2PGL

Catalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.211 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Liu, Q.Kriksunov, I.A.Moreau, C.Graeff, R.Potter, B.V.Lee, H.C.Hao, Q.

(2007) J Biol Chem 282: 24825-24832

  • DOI: https://doi.org/10.1074/jbc.M701653200
  • Primary Citation of Related Structures:  
    2PGJ, 2PGL

  • PubMed Abstract: 

    Cyclic ADP-ribose (cADPR) is a calcium mobilization messenger important for mediating a wide range of physiological functions. The endogenous levels of cADPR in mammalian tissues are primarily controlled by CD38, a multifunctional enzyme capable of both synthesizing and hydrolyzing cADPR. In this study, a novel non-hydrolyzable analog of cADPR, N1-cIDPR (N1-cyclic inosine diphosphate ribose), was utilized to elucidate the structural determinants involved in the hydrolysis of cADPR. N1-cIDPR inhibits CD38-catalyzed cADPR hydrolysis with an IC(50) of 0.26 mM. N1-cIDPR forms a complex with CD38 or its inactive mutant in which the catalytic residue Glu-226 is mutated. Both complexes have been determined by x-ray crystallography at 1.7 and 1.76 A resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 A) with Glu-226, confirming our previously proposed model for cADPR catalysis. Structural analyses reveal that both the enzyme and substrate cADPR undergo catalysis-associated conformational changes. From the enzyme side, residues Glu-146, Asp-147, and Trp-125 work collaboratively to facilitate the formation of the Michaelis complex. From the substrate side, cADPR is found to change its conformation to fit into the active site until it reaches the catalytic residue. The binary CD38-cADPR model described here represents the most detailed description of the CD38-catalyzed hydrolysis of cADPR at atomic resolution. Our structural model should provide insights into the design of effective cADPR analogs.


  • Organizational Affiliation

    MacCHESS, Cornell High Energy Synchrotron Source, Cornell University, Ithaca, New York 14853, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ADP-ribosyl cyclase 1
A, B
262Homo sapiensMutation(s): 6 
Gene Names: CD38
EC: 3.2.2.5
UniProt & NIH Common Fund Data Resources
Find proteins for P28907 (Homo sapiens)
Explore P28907 
Go to UniProtKB:  P28907
PHAROS:  P28907
GTEx:  ENSG00000004468 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28907
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
N1C
Query on N1C

Download Ideal Coordinates CCD File 
C [auth A]N1-CYCLIC INOSINE 5'-DIPHOSPHORIBOSE
C15 H20 N4 O14 P2
REBZYOYBILSKBL-ATYUDWGKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
N1C PDBBind:  2PGL IC50: 2.60e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.211 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.866α = 105.79
b = 53.195β = 92.07
c = 65.706γ = 95.2
Software Package:
Software NamePurpose
REFMACrefinement
ADSCdata collection
HKL-3000data reduction
HKL-3000data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-04-24
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description