3I9M

Crystal structure of human CD38 complexed with an analog ara-2'F-ADPR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase

Liu, Q.Graeff, R.Kriksunov, I.A.Jiang, H.Zhang, B.Oppenheimer, N.Lin, H.Potter, B.V.L.Lee, H.C.Hao, Q.

(2009) J Biol Chem 284: 27637-27645

  • DOI: https://doi.org/10.1074/jbc.M109.031005
  • Primary Citation of Related Structures:  
    3I9J, 3I9K, 3I9L, 3I9M, 3I9N

  • PubMed Abstract: 

    Cyclic ADP-ribose (cADPR) is a universal calcium messenger molecule that regulates many physiological processes. The production and degradation of cADPR are catalyzed by a family of related enzymes, including the ADP-ribosyl cyclase from Aplysia california (ADPRAC) and CD38 from human. Although ADPRC and CD38 share a common evolutionary ancestor, their enzymatic functions toward NAD and cADPR homeostasis have evolved divergently. Thus, ADPRC can only generate cADPR from NAD (cyclase), whereas CD38, in contrast, has multiple activities, i.e. in cADPR production and degradation, as well as NAD hydrolysis (NADase). In this study, we determined a number of ADPRC and CD38 structures bound with various nucleotides. From these complexes, we elucidated the structural features required for the cyclization (cyclase) reaction of ADPRC and the NADase reaction of CD38. Using the structural approach in combination with site-directed mutagenesis, we identified Phe-174 in ADPRC as a critical residue in directing the folding of the substrate during the cyclization reaction. Thus, a point mutation of Phe-174 to glycine can turn ADPRC from a cyclase toward an NADase. The equivalent residue in CD38, Thr-221, is shown to disfavor the cyclizing folding of the substrate, resulting in NADase being the dominant activity. The comprehensive structural comparison of CD38 and APDRC presented in this study thus provides insights into the structural determinants for the functional evolution from a cyclase to a hydrolase.


  • Organizational Affiliation

    MacCHESS, Cornell High Energy Synchrotron Source, CornellUniversity, 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): 5 
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AVU
Query on AVU

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl [(2R,3R,4R)-4-fluoro-3-hydroxytetrahydrofuran-2-yl]methyl dihydrogen diphosphate
C15 H22 F N5 O12 P2
GOCJJDZHXMDJEZ-WFCIOUKESA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.635α = 106.34
b = 52.725β = 92.05
c = 65.26γ = 95.11
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-11-10
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-11-01
    Changes: Data collection, Refinement description