2O3T

Structural Basis for Formation and Hydrolysis of Calcium Messenger Cyclic ADP-ribose by Human CD38

Summary for 2O3T

• Entry DOI: 10.2210/pdb2o3t/pdb
• Related: 1YH3 2O3Q 2O3R 2O3S 2O3U
• Descriptor: ADP-ribosyl cyclase 1, CYCLIC GUANOSINE DIPHOSPHATE-RIBOSE (3 entities in total)
• Functional Keywords: human cd38 e226q mutant, the catalytic pocket, cgdpr formation and hydrolysis, substrate binding, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type II membrane protein: P28907
• Total number of polymer chains: 2
• Total formula weight: 61318.13

Authors

Liu, Q.,Kriksunov, I.A.,Graeff, R.,Lee, H.C.,Hao, Q. (deposition date: 2006-12-01, release date: 2006-12-19, Last modification date: 2024-11-20)

Primary citation

Liu, Q.,Kriksunov, I.A.,Graeff, R.,Lee, H.C.,Hao, Q.
Structural basis for formation and hydrolysis of the calcium messenger cyclic ADP-ribose by human CD38
J.Biol.Chem., 282:5853-5861, 2007

PubMed Abstract: Human CD38 is a multifunctional ectoenzyme responsible for catalyzing the conversions from nicotinamide adenine dinucleotide (NAD) to cyclic ADP-ribose (cADPR) and from cADPR to ADP-ribose (ADPR). Both cADPR and ADPR are calcium messengers that can mobilize intracellular stores and activate influx as well. In this study, we determined three crystal structures of the human CD38 enzymatic domain complexed with cADPR at 1.5-A resolution, with its analog, cyclic GDP-ribose (cGDPR) (1.68 A) and with NGD (2.1 A) a substrate analog of NAD. The results indicate that the binding of cADPR or cGDPR to the active site induces structural rearrangements in the dipeptide Glu(146)-Asp(147) by as much as 2.7 A) providing the first direct evidence of a conformational change at the active site during catalysis. In addition, Glu(226) is shown to be critical not only in catalysis but also in positioning of cADPR at the catalytic site through strong hydrogen bonding interactions. Structural details obtained from these complexes provide a step-by-step description of the catalytic processes in the synthesis and hydrolysis of cADPR.

PubMed: 17182614
DOI: 10.1074/jbc.M609093200

Experimental method

X-RAY DIFFRACTION (1.68 Å)