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{{STRUCTURE_4kl9|  PDB=4kl9  |  SCENE=  }}
==Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in the space group C2==
===Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in the space group C2===
<StructureSection load='4kl9' size='340' side='right' caption='[[4kl9]], [[Resolution|resolution]] 1.39&Aring;' scene=''>
{{ABSTRACT_PUBMED_24210757}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4kl9]] 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=4KL9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KL9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4klx|4klx]], [[4km0|4km0]], [[4km2|4km2]], [[4kne|4kne]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dfrA, folA, MT2833, MTV002.28c, Rv2763c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4kl9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kl9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kl9 RCSB], [http://www.ebi.ac.uk/pdbsum/4kl9 PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/DYR_MYCTU DYR_MYCTU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibition of the biosynthesis of tetrahydrofolate (THF) has long been a focus in the treatment of both cancer and infectious diseases. Dihydrofolate reductase (DHFR), which catalyzes the last step, is one of the most thoroughly explored targets of this pathway, but there are no DHFR inhibitors used for tuberculosis treatment. Here, we report a structural, site-directed mutagenesis and calorimetric analysis of Mycobacterium tuberculosis DHFR (MtDHFR) in complex with classical DHFR inhibitors. Our study provides insights into the weak inhibition of MtDHFR by trimethoprim and other antifolate drugs, such as pyrimethamine and cycloguanil. The construction of the mutant Y100F, together with calorimetric studies, gives insights into low affinity of MtDHFR for classical DHFR inhibitors. Finally, the structures of MtDHFR in complex with pyrimethamine and cycloguanil define important interactions in the active site and provide clues to the more effective design of antibiotics targeted against MtDHFR.


==Function==
Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs.,Dias MV, Tyrakis P, Domingues RR, Leme AF, Blundell TL Structure. 2013 Nov 6. pii: S0969-2126(13)00395-X. doi:, 10.1016/j.str.2013.09.022. PMID:24210757<ref>PMID:24210757</ref>
[[http://www.uniprot.org/uniprot/DYR_MYCTU DYR_MYCTU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4kl9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KL9 OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:024210757</ref><references group="xtra"/><references/>
*[[Dihydrofolate reductase|Dihydrofolate reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dihydrofolate reductase]]
[[Category: Dihydrofolate reductase]]
[[Category: Blundell, T L.]]
[[Category: Blundell, T L]]
[[Category: Dias, M V.B]]
[[Category: Dias, M V.B]]
[[Category: Tyrakis, P.]]
[[Category: Tyrakis, P]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Reductase]]
[[Category: Reductase]]

Revision as of 10:56, 24 December 2014

Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in the space group C2Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in the space group C2

Structural highlights

4kl9 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:,
Gene:dfrA, folA, MT2833, MTV002.28c, Rv2763c ("Bacillus tuberculosis" (Zopf 1883) Klein 1884)
Activity:Dihydrofolate reductase, with EC number 1.5.1.3
Resources:FirstGlance, OCA, RCSB, PDBsum

Function

[DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.

Publication Abstract from PubMed

Inhibition of the biosynthesis of tetrahydrofolate (THF) has long been a focus in the treatment of both cancer and infectious diseases. Dihydrofolate reductase (DHFR), which catalyzes the last step, is one of the most thoroughly explored targets of this pathway, but there are no DHFR inhibitors used for tuberculosis treatment. Here, we report a structural, site-directed mutagenesis and calorimetric analysis of Mycobacterium tuberculosis DHFR (MtDHFR) in complex with classical DHFR inhibitors. Our study provides insights into the weak inhibition of MtDHFR by trimethoprim and other antifolate drugs, such as pyrimethamine and cycloguanil. The construction of the mutant Y100F, together with calorimetric studies, gives insights into low affinity of MtDHFR for classical DHFR inhibitors. Finally, the structures of MtDHFR in complex with pyrimethamine and cycloguanil define important interactions in the active site and provide clues to the more effective design of antibiotics targeted against MtDHFR.

Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs.,Dias MV, Tyrakis P, Domingues RR, Leme AF, Blundell TL Structure. 2013 Nov 6. pii: S0969-2126(13)00395-X. doi:, 10.1016/j.str.2013.09.022. PMID:24210757[1]

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

See Also

References

  1. ↑ Dias MV, Tyrakis P, Domingues RR, Leme AF, Blundell TL. Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs. Structure. 2013 Nov 6. pii: S0969-2126(13)00395-X. doi:, 10.1016/j.str.2013.09.022. PMID:24210757 doi:http://dx.doi.org/10.1016/j.str.2013.09.022

4kl9, resolution 1.39Å

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