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1n5i

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Revision as of 18:48, 20 November 2019

CRYSTAL STRUCTURE OF INACTIVE MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH THYMIDINE MONOPHOSPHATE (TMP) AT PH 4.6 (RESOLUTION 1.85 A)

Structural highlights

1n5i is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	1gsi, 1g3u, 1n5j, 1n5k, 1n5l
Activity:	dTMP kinase, with EC number 2.7.4.9
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KTHY_MYCTU] Catalyzes the reversible phosphorylation of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), using ATP as its preferred phosphoryl donor. Situated at the junction of both de novo and salvage pathways of deoxythymidine triphosphate (dTTP) synthesis, is essential for DNA synthesis and cellular growth. Has a broad specificity for nucleoside triphosphates, being highly active with ATP or dATP as phosphate donors, and less active with ITP, GTP, CTP and UTP.[HAMAP-Rule:MF_00165]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Mycobacterium tuberculosis TMP kinase (TMPK(Mtub)) represents a promising target for developing drugs against tuberculosis because the configuration of its active site is unique in the TMPK family. To help elucidate the phosphorylation mechanism employed by this enzyme, structural changes occurring upon binding of substrates and subsequent catalysis were investigated by protein crystallography. Six new structures of TMPK(Mtub) were solved at a resolution better than 2.3A, including the first structure of an apo-TMPK, obtained by triggering catalysis in a crystal of a TMPK(Mtub)-TMP complex, which resulted in the release of the TDP product. A series of snapshots along the reaction pathway is obtained, revealing the closure of the active site in going from an empty to a fully occupied state, suggestive of an induced-fit mechanism typical of NMPKs. However, in TMPK(Mtub) the LID closure couples to the binding with an unusual location for a magnesium ion coordinating TMP in the active site. Our data suggest strongly that this ion is required for catalysis, acting as a clamp, possibly in concert with Arg95, to neutralise electrostatic repulsion between the anionic substrates, optimise their proper alignment and activate them through direct and water-mediated interactions. The 3'-hydroxyl moiety of TMP, critical to metal stabilisation, appears to be a target of choice for the design of potent inhibitors. On the other hand, the usual NTP-bound magnesium is not seen in our structures and Arg14, a P-loop residue unique to TMPK(Mtub), may take over its role. Therefore, TMPK(Mtub) seems to have swapped the use of a metal ion as compared with e.g. human TMPK. Finally, TTP was observed in crystals of TMPK(Mtub), locked by Arg14, thus providing a structural explanation for the observed inhibitory effect of TTP putatively involved in a mechanism of feedback regulation of the enzymatic activity.

Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway.,Fioravanti E, Haouz A, Ursby T, Munier-Lehmann H, Delarue M, Bourgeois D J Mol Biol. 2003 Apr 11;327(5):1077-92. PMID:12662932^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Fioravanti E, Haouz A, Ursby T, Munier-Lehmann H, Delarue M, Bourgeois D. Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway. J Mol Biol. 2003 Apr 11;327(5):1077-92. PMID:12662932

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1n5i"

@@ Line 1: / Line 1: @@
 ==CRYSTAL STRUCTURE OF INACTIVE MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH THYMIDINE MONOPHOSPHATE (TMP) AT PH 4.6 (RESOLUTION 1.85 A)==
-<StructureSection load='1n5i' size='340' side='right' caption='[[1n5i]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
+<StructureSection load='1n5i' size='340' side='right'caption='[[1n5i]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1n5i]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N5I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1N5I FirstGlance]. <br>
@@ Line 30: / Line 30: @@
 </div>
 <div class="pdbe-citations 1n5i" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Thymidylate kinase|Thymidylate kinase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: DTMP kinase]]
 [[Category: Bourgeois, D]]

1n5i

From Proteopedia

Revision as of 18:48, 20 November 2019

CRYSTAL STRUCTURE OF INACTIVE MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH THYMIDINE MONOPHOSPHATE (TMP) AT PH 4.6 (RESOLUTION 1.85 A)

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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