PDBsum entry 5mql

Transferase

PDB id: 5mql

Contents

Protein chains

231 a.a.

Ligands

UDP ×4

G65

DCM ×2

Metals

_MG

Waters ×18

PDB id:

5mql

Name:

Transferase

Title:

Crystal structure of dck mutant c3s in complex with masitinib and udp

Structure:

Deoxycytidine kinase. Chain: a, b, c, d. Synonym: dck. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dck. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.25Å R-factor: 0.219 R-free: 0.277

Authors:

E.Rebuffet,K.Hammam,M.Saez-Ayala,L.Gros,S.Lopez,B.Hajem,M.Humbert, E.Baudelet,S.Audebert,S.Betzi,A.Lugari,S.Combes,D.Pez,S.Letard, C.Mansfield,A.Moussy,P.De Sepulveda,X.Morelli,P.Dubreuil

Key ref:

K.Hammam et al. (2017). Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology. Nat Commun, 8, 1420. PubMed id: 29127277

Date:

20-Dec-16 Release date: 22-Nov-17

Protein chains

P27707  (DCK_HUMAN) -  Deoxycytidine kinase from Homo sapiens

Seq: 260 a.a.

Struc: 231 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: E.C.2.7.1.113 - deoxyguanosine kinase.
• Reaction: 2'-deoxyguanosine + ATP = dGMP + ADP + H⁺

2'-deoxyguanosine + ATP = dGMP (Bound ligand (Het Group name = UDP) matches with 79.31% similarity) + ADP (Bound ligand (Het Group name = DCM) matches with 72.00% similarity) + H(+)

• Enzyme class 3: E.C.2.7.1.74 - deoxycytidine kinase.
• Reaction: 2'-deoxycytidine + a ribonucleoside 5'-triphosphate = dCMP + a ribonucleoside 5'-diphosphate + H⁺

2'-deoxycytidine + ribonucleoside 5'-triphosphate = dCMP + ribonucleoside 5'-diphosphate (Bound ligand (Het Group name = DCM) corresponds exactly) + H(+)

• Enzyme class 4: E.C.2.7.1.76 - deoxyadenosine kinase.
• Reaction: 2'-deoxyadenosine + ATP = dAMP + ADP + H⁺

2'-deoxyadenosine (Bound ligand (Het Group name = DCM) matches with 65.22% similarity) + ATP = dAMP (Bound ligand (Het Group name = UDP) matches with 79.31% similarity) + ADP + 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

Nat Commun 8:1420 (2017)

PubMed id: 29127277

Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology.

K.Hammam, M.Saez-Ayala, E.Rebuffet, L.Gros, S.Lopez, B.Hajem, M.Humbert, E.Baudelet, S.Audebert, S.Betzi, A.Lugari, S.Combes, S.Letard, N.Casteran, C.Mansfield, A.Moussy, P.De Sepulveda, X.Morelli, P.Dubreuil.

ABSTRACT

Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.