PDBsum entry 4tmf

Hydrolase/hydrolase inhibitor

PDB id: 4tmf

Contents

Protein chains

244 a.a.

Ligands

JS2 ×2

Waters ×80

PDB id:

4tmf

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of human cd38 in complex with hydrolysed compound jms713

Structure:

Adp-ribosyl cyclase/cyclic adp-ribose hydrolase 1. Chain: a, b. Fragment: ecto domain. Synonym: 2'-phospho-adp-ribosyl cyclase,2'-phospho-adp-ribosyl cyclase/2'-phospho-cyclic-adp-ribose transferase,2'-phospho-cyclic- adp-ribose transferase,adp-ribosyl cyclase 1,adprc 1,cyclic adp- ribose hydrolase 1,cadpr hydrolase 1,t10. Engineered: yes. Mutation: yes

Source:

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

Resolution:

2.05Å R-factor: 0.200 R-free: 0.227

Authors:

H.Zhang,J.Swarbrick,B.Potter,Q.Hao

Key ref:

J.M.Swarbrick et al. (2014). Cyclic adenosine 5'-diphosphate ribose analogs without a "southern" ribose inhibit ADP-ribosyl cyclase-hydrolase CD38. J Med Chem, 57, 8517-8529. PubMed id: 25226087 DOI: 10.1021/jm501037u

Date:

01-Jun-14 Release date: 13-May-15

Protein chains

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

Seq: 300 a.a.

Struc: 244 a.a.*

* PDB and UniProt seqs differ at 5 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⁺

NAD(+) + H2O = ADP-D-ribose (Bound ligand (Het Group name = JS2) matches with 46.81% similarity) + 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

DOI no: 10.1021/jm501037u

J Med Chem 57:8517-8529 (2014)

PubMed id: 25226087

Cyclic adenosine 5'-diphosphate ribose analogs without a "southern" ribose inhibit ADP-ribosyl cyclase-hydrolase CD38.

J.M.Swarbrick, R.Graeff, H.Zhang, M.P.Thomas, Q.Hao, B.V.Potter.

ABSTRACT

Cyclic adenosine 5'-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5'-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the nonessential nature of the "southern" ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs, and 8-amino-N9-butyl-cIDPR is comparable to the best noncovalent CD38 inhibitors to date (IC50 = 3.3 μM). Crystallographic analysis of the shCD38:8-amino-N9-butyl-cIDPR complex to a 2.05 Å resolution unexpectedly reveals an N1-hydrolyzed ligand in the active site, suggesting that it is the N6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the "northern" ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38, and may aid future inhibitor design.