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[[Image:5mdh.gif|left|200px]]
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{{STRUCTURE_5mdh|  PDB=5mdh  |  SCENE=  }}
'''CRYSTAL STRUCTURE OF TERNARY COMPLEX OF PORCINE CYTOPLASMIC MALATE DEHYDROGENASE ALPHA-KETOMALONATE AND TNAD AT 2.4 ANGSTROMS RESOLUTION'''


==CRYSTAL STRUCTURE OF TERNARY COMPLEX OF PORCINE CYTOPLASMIC MALATE DEHYDROGENASE ALPHA-KETOMALONATE AND TNAD AT 2.4 ANGSTROMS RESOLUTION==
<StructureSection load='5mdh' size='340' side='right'caption='[[5mdh]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5mdh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. The October 2012 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Citric Acid Cycle''  by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2012_10 10.2210/rcsb_pdb/mom_2012_10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MDH FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAK:ALPHA-KETOMALONIC+ACID'>MAK</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></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=5mdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mdh OCA], [https://pdbe.org/5mdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mdh RCSB], [https://www.ebi.ac.uk/pdbsum/5mdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mdh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MDHC_PIG MDHC_PIG]
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/md/5mdh_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=5mdh ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The structural basis for the extreme discrimination achieved by malate dehydrogenases between a variety of closely related substrates encountered within the cell has been difficult to assess because of the lack of an appropriate catalytically competent structure of the enzyme. Here, we have determined the crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase with the alternative substrate alpha-ketomalonate and the coenzyme analogue 1,4,5,6-tetrahydronicotinamide. Both subunits of the dimeric porcine heart, and from the prokaryotes Escherichia coli and Thermus flavus. However, large changes are noted around the active site, where a mobile loop now closes to bring key residues into contact with the substrate. This observation substantiates a postulated mechanism in which the enzyme achieves high levels of substrate discrimination through charge balancing in the active site. As the activated cofactor/substrate complex has a net negative charge, a positive counter-charge is provided by a conserved arginine in the active site loop. The enzyme must, however, also discriminate against smaller substrates, such as pyruvate. The structure shows in the closed (loop down) catalytically competent complex two arginine residues (91 and 97) are driven into close proximity. Without the complimentary, negative charge of the substrate side-chain of oxaloacetate or alpha-ketomalonate, charge repulsion would resist formation production of this catalytically productive conformation, hence minimising the effectiveness of pyruvate as a substrate. By this mechanism, malate dehydrogenase uses charge balancing to achieve fivefold orders of magnitude in discrimination between potential substrates.


==Overview==
Structural basis of substrate specificity in malate dehydrogenases: crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase, alpha-ketomalonate and tetrahydoNAD.,Chapman AD, Cortes A, Dafforn TR, Clarke AR, Brady RL J Mol Biol. 1999 Jan 15;285(2):703-12. PMID:10075524<ref>PMID:10075524</ref>
The structural basis for the extreme discrimination achieved by malate dehydrogenases between a variety of closely related substrates encountered within the cell has been difficult to assess because of the lack of an appropriate catalytically competent structure of the enzyme. Here, we have determined the crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase with the alternative substrate alpha-ketomalonate and the coenzyme analogue 1,4,5,6-tetrahydronicotinamide. Both subunits of the dimeric porcine heart, and from the prokaryotes Escherichia coli and Thermus flavus. However, large changes are noted around the active site, where a mobile loop now closes to bring key residues into contact with the substrate. This observation substantiates a postulated mechanism in which the enzyme achieves high levels of substrate discrimination through charge balancing in the active site. As the activated cofactor/substrate complex has a net negative charge, a positive counter-charge is provided by a conserved arginine in the active site loop. The enzyme must, however, also discriminate against smaller substrates, such as pyruvate. The structure shows in the closed (loop down) catalytically competent complex two arginine residues (91 and 97) are driven into close proximity. Without the complimentary, negative charge of the substrate side-chain of oxaloacetate or alpha-ketomalonate, charge repulsion would resist formation production of this catalytically productive conformation, hence minimising the effectiveness of pyruvate as a substrate. By this mechanism, malate dehydrogenase uses charge balancing to achieve fivefold orders of magnitude in discrimination between potential substrates.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
5MDH is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MDH OCA].
</div>
<div class="pdbe-citations 5mdh" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Structural basis of substrate specificity in malate dehydrogenases: crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase, alpha-ketomalonate and tetrahydoNAD., Chapman AD, Cortes A, Dafforn TR, Clarke AR, Brady RL, J Mol Biol. 1999 Jan 15;285(2):703-12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10075524 10075524]
*[[Malate Dehydrogenase 3D structures|Malate Dehydrogenase 3D structures]]
[[Category: Malate dehydrogenase]]
== References ==
[[Category: Single protein]]
<references/>
__TOC__
</StructureSection>
[[Category: Citric Acid Cycle]]
[[Category: Large Structures]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
[[Category: Brady, R L.]]
[[Category: Brady RL]]
[[Category: Chapman, A D.M.]]
[[Category: Chapman ADM]]
[[Category: Clarke, A R.]]
[[Category: Clarke AR]]
[[Category: Cortes, A.]]
[[Category: Cortes A]]
[[Category: Dafforn, T R.]]
[[Category: Dafforn TR]]
[[Category: Oxidoreductase]]
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Retrieved from "https://proteopedia.org/5mdh"