PDBsum entry 1w2g

Transferase

PDB id

1w2g

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Contents

			Protein chains

					197 a.a. *

			Ligands

					ACT ×3


					THM ×2

			Waters ×153

* Residue conservation analysis

PDB id:

1w2g

Links

Name:

Transferase

Title:

Crystal structure of mycobacterium tuberculosis thymidylate kinase complexed with deoxythymidine (dt) (2.1 a resolution)

Structure:

Thymidylate kinase tmk. Chain: a, b. Synonym: dtmp kinase, thymidylic acid kinase, tmpk. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 1773. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.10Å

R-factor:

0.211

R-free:

0.244

Authors:

E.Fioravanti,V.Adam,H.Munier-Lehmann,D.Bourgeois

Key ref:

E.Fioravanti et al. (2005). The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition. Biochemistry, 44, 130-137. PubMed id: 15628853 DOI: 10.1021/bi0484163

Date:

06-Jul-04

Release date:

12-Jan-05

PROCHECK

	Headers

	References

Protein chains

P9WKE1 (KTHY_MYCTU) - Thymidylate kinase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: Struc:					214 a.a. 197 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.7.4.9 - dTMP kinase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

dTMP + ATP = dTDP + ADP

dTMP

ATP
Bound ligand (Het Group name = THM)
matches with 80.95% similarity

dTDP

ADP

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

reference

DOI no: 10.1021/bi0484163	Biochemistry 44:130-137 (2005)
PubMed id: 15628853

The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition.
E.Fioravanti, V.Adam, H.Munier-Lehmann, D.Bourgeois.

ABSTRACT

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis thymidylate kinase (TMPK(Mtub)) catalyzes the ATP-dependent phosphorylation of deoxythymidine 5'-monophosphate (dTMP). Essential to DNA replication, this enzyme represents a promising target for developing new drugs against TB, because the configuration of its active site is unique within the TMPK family. Indeed, it has been proposed that, as opposed to other TMPKs, catalysis by TMPK(Mtub) necessitates the transient binding of a magnesium ion coordinating the phosphate acceptor. Moreover, 3'-azidodeoxythymidine monophosphate (AZTMP) is a competitive inhibitor of TMPK(Mtub), whereas it is a substrate for human and other TMPKs. Here, the crystal structures of TMPK(Mtub) in complex with deoxythymidine (dT) and AZTMP were determined to 2.1 and 2.0 A resolution, respectively, and suggest a mechanism for inhibition. The azido group of AZTMP perturbs the induced-fit mechanism normally adopted by the enzyme. Magnesium is prevented from binding, and the resulting electrostatic environment precludes phosphoryl transfer from occurring. Our data provide a model for drug development against tuberculosis.

Literature references that cite this PDB file's key reference

PubMed id

Reference

18523102

C.Carnrot, L.Wang, D.Topalis, and S.Eriksson (2008).
Mechanisms of substrate selectivity for Bacillus anthracis thymidylate kinase.

Protein Sci, 17, 1486-1493.

18418833

O.Familiar, H.Munier-Lehmann, A.Negri, F.Gago, D.Douguet, L.Rigouts, A.I.Hernández, M.J.Camarasa, and M.J.Pérez-Pérez (2008).
Exploring acyclic nucleoside analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase.

ChemMedChem, 3, 1083-1093.

17141524

N.Couto, M.F.Duarte, M.T.Fernandez, P.Rodrigues, M.T.Barros, M.L.Costa, and B.J.Cabral (2007).
Complexation of transition metals by 3-azidopropionitrile. An electrospray ionization mass spectrometry study.

J Am Soc Mass Spectrom, 18, 453-465.

16288457

G.Hible, P.Christova, L.Renault, E.Seclaman, A.Thompson, E.Girard, H.Munier-Lehmann, and J.Cherfils (2006).
Unique GMP-binding site in Mycobacterium tuberculosis guanosine monophosphate kinase.

Proteins, 62, 489-500.

PDB codes:

1znw 1znx 1zny 1znz

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.