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==Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in complex with pyrimethamine==
==Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in complex with pyrimethamine==
<StructureSection load='4km0' size='340' side='right' caption='[[4km0]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
<StructureSection load='4km0' size='340' side='right'caption='[[4km0]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4km0]] is a 2 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=4KM0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KM0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4km0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KM0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KM0 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATR:2-MONOPHOSPHOADENOSINE-5-DIPHOSPHATE'>ATR</scene>, <scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4kl9|4kl9]], [[4klx|4klx]], [[4km2|4km2]], [[4kne|4kne]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATR:2-MONOPHOSPHOADENOSINE-5-DIPHOSPHATE'>ATR</scene>, <scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4km0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4km0 OCA], [https://pdbe.org/4km0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4km0 RCSB], [https://www.ebi.ac.uk/pdbsum/4km0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4km0 ProSAT]</span></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=4km0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4km0 OCA], [http://pdbe.org/4km0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4km0 RCSB], [http://www.ebi.ac.uk/pdbsum/4km0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4km0 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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.
[https://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.


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>
==See Also==
 
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4km0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dihydrofolate reductase]]
[[Category: Large Structures]]
[[Category: Blundell, T L]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Dias, M V.B]]
[[Category: Blundell TL]]
[[Category: Tyrakis, P]]
[[Category: Dias MVB]]
[[Category: Oxidoreductase]]
[[Category: Tyrakis P]]
[[Category: Reductase]]

Latest revision as of 15:13, 1 March 2024

Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in complex with pyrimethamineCrystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in complex with pyrimethamine

Structural highlights

4km0 is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.3Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

See Also

4km0, resolution 1.30Å

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