6ecq: Difference between revisions

<table><tr><td colspan='2'>[[6ecq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ECQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ECQ FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LUD:N-{4-[(6aR)-3-amino-1,9-dioxo-1,2,5,6,6a,7-hexahydroimidazo[1,5-f]pteridin-8(9H)-yl]benzene-1-carbonyl}-L-glutamic+acid'>LUD</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>

<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MTHFD1, MTHFC, MTHFD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ecq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ecq OCA], [http://pdbe.org/6ecq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ecq RCSB], [http://www.ebi.ac.uk/pdbsum/6ecq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ecq ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/C1TC_HUMAN C1TC_HUMAN]] Defects in MTHFD1 may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM:[http://omim.org/entry/601634 601634]]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Genetic defects in MTHFD1 may affect the risk of spina bifida via the maternal rather than the embryonic genotype.<ref>PMID:9611072</ref> <ref>PMID:12384833</ref> <ref>PMID:16552426</ref>  Genetic variation in MTHFD1 could be associated with susceptibility to colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]].

Enzymes involved in tetrahydrofolate metabolism are of particular pharmaceutical interest, as their function is crucial for amino acid and DNA biosynthesis. The crystal structure of the human cytosolic methylenetetrahydrofolate dehydrogenase/cyclohydrolase (DC301) domain of a trifunctional enzyme has been determined previously with a bound NADP cofactor. While the substrate binding site was identified to be localized in a deep and rather hydrophobic cleft at the interface between two protein domains, the unambiguous assignment of catalytic residues was not possible. We succeeded in determining the crystal structures of three ternary DC301/NADP/inhibitor complexes. Investigation of these structures followed by site-directed mutagenesis studies allowed identification of the amino acids involved in catalysis by both enzyme activities. The inhibitors bind close to Lys56 and Tyr52, residues of a strictly conserved motif for active sites in dehydrogenases. While Lys56 is in a good position for chemical interaction with the substrate analogue, Tyr52 was found stacking against the inhibitors' aromatic rings and hence seems to be more important for proper positioning of the ligand than for catalysis. Also, Ser49 and/or Cys147 were found to possibly act as an activator for water in the cyclohydrolase step. These and the other residues (Gln100 and Asp125), with which contacts are made, are strictly conserved in THF dehydrogenases. On the basis of structural and mutagenesis data, we propose a reaction mechanism for both activities, the dehydrogenase and the cyclohydrolase.

Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.,Schmidt A, Wu H, MacKenzie RE, Chen VJ, Bewly JR, Ray JE, Toth JE, Cygler M Biochemistry. 2000 May 30;39(21):6325-35. PMID:10828945<ref>PMID:10828945</ref>

[[Category: Human]]

[[Category: Bueno, R V]]

[[Category: Dawson, A]]

[[Category: Hunter, W N]]

[[Category: Oxidoreductase]]