PDBsum entry 3f6y

Hydrolase

PDB id: 3f6y

Contents

Protein chain

235 a.a. *

Metals

_CA ×3

Waters ×285

* Residue conservation analysis

PDB id:

3f6y

Name:

Hydrolase

Title:

Conformational closure of the catalytic site of human cd38 induced by calcium

Structure:

Adp-ribosyl cyclase 1. Chain: a. Fragment: enzymatic domain, extracellular domain. Synonym: cyclic adp-ribose hydrolase 1, cadpr hydrolase 1, t10, cd38 antigen. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cd38. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Resolution:

1.45Å R-factor: 0.148 R-free: 0.184

Authors:

Q.Liu,R.Graeff,I.A.Kriksunov,C.M.C.Lam,H.C.Lee,Q.Hao

Key ref:

Q.Liu et al. (2008). Conformational Closure of the Catalytic Site of Human CD38 Induced by Calcium. Biochemistry, 47, 13966-13973. PubMed id: 19117080

Date:

07-Nov-08 Release date: 18-Nov-08

Protein chain

P28907  (CD38_HUMAN) -  ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 from Homo sapiens

Seq: 300 a.a.

Struc: 235 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.4.99.20 - 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase.
• Reaction: nicotinate + NADP⁺ = nicotinate-adenine dinucleotide phosphate + nicotinamide
• Enzyme class 2: E.C.3.2.2.- - ?????
• Enzyme class 3: E.C.3.2.2.6 - ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase.
• Reaction: NAD⁺ + H2O = ADP-D-ribose + nicotinamide + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Biochemistry 47:13966-13973 (2008)

PubMed id: 19117080

Conformational Closure of the Catalytic Site of Human CD38 Induced by Calcium.

Q.Liu, R.Graeff, I.A.Kriksunov, C.M.Lam, H.C.Lee, Q.Hao.

ABSTRACT

First identified on the surface of lymphoids as a type II transmembrane protein, CD38 has now been established to have dual functions not only as a receptor but also as a multifunctional enzyme,catalyzing the synthesis of and hydrolysis of a general calcium messenger molecule, cyclic ADP-ribose(cADPR). The receptorial functions of CD38 include the induction of cell adhesion, differentiation,apoptosis, and cytokine production upon antibody ligation. Here we determined the crystal structure of calcium-loaded human CD38 at 1.45 A resolution which reveals that CD38 undergoes dramatic structural changes to an inhibited conformation in the presence of calcium. The structural changes are highly localized and occur in only two regions. The first region is part of the active site and consists of residues 121-141.In the presence of calcium, W125 moves 5 A into the active site and forms hydrophobic interactions with W189. The movement closes the active site pocket and reduces entry of substrates, resulting in inhibition of the enzymatic activity. The structural role of calcium in inducing these conformational changes is readily visualized in the crystal structure. The other region that undergoes calcium-induced changes is at the receptor region, where a highly ordered helix is unraveled to a random coil. The results suggest a novel conformational coupling mechanism, whereby protein interaction targeted at the receptor region can effectively regulate the enzymatic activity of CD38.