View source for 2qtl


==Crystal Structure of the FAD-containing FNR-like Module of Human Methionine Synthase Reductase==
<StructureSection load='2qtl' size='340' side='right'caption='[[2qtl]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2qtl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QTL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QTL 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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=2qtl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qtl OCA], [https://pdbe.org/2qtl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qtl RCSB], [https://www.ebi.ac.uk/pdbsum/2qtl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qtl ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MTRR_HUMAN MTRR_HUMAN] Defects in MTRR are the cause of methylcobalamin deficiency type E (cblE) [MIM:[https://omim.org/entry/236270 236270]; also known as vitamin B12-responsive homocystinuria or homocystinuria-megaloblastic anemia complementation type E. Patients who are defective in reductive activation of methionine synthase exhibit megaloblastic anemia, developmental delay, hypomethioninemia, and hyperhomocysteinemia, a risk factor in cardiovascular disease and neural tube defects. It is an autosomal recessive disease.  Defects in MTRR may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM:[https://omim.org/entry/601634 601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Genetic defects in MTRR may affect the risk of spina bifida via the maternal rather than the embryonic genotype.<ref>PMID:10444342</ref> <ref>PMID:12375236</ref> <ref>PMID:15979034</ref> 
== Function ==
[https://www.uniprot.org/uniprot/MTRR_HUMAN MTRR_HUMAN] Involved in the reductive regeneration of cob(I)alamin cofactor required for the maintenance of methionine synthase in a functional state.
== 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/qt/2qtl_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=2qtl ConSurf].
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== Publication Abstract from PubMed ==
Human methionine synthase reductase (MSR) is a 78 kDa flavoprotein that regenerates the active form of cobalamin-dependent methionine synthase (MS). MSR contains one FAD and one FMN cofactor per polypeptide and functions in the sequential transfer of reducing equivalents from NADPH to MS via its flavin centers. We report the 1.9 A crystal structure of the NADP+-bound FNR-like module of MSR that spans the NADP(H)-binding domain, the FAD-binding domain, the connecting domain, and part of the extended hinge region, a feature unique to MSR. The overall fold of the protein is similar to that of the corresponding domains of the related diflavin reductase enzymes cytochrome P450 reductase and neuronal nitric oxide synthase (NOS). However, the extended hinge region of MSR, which is positioned between the NADP(H)/FAD- and FMN-binding domains, is in an unexpected orientation with potential implications for the mechanism of electron transfer. Compared with related flavoproteins, there is structural variation in the NADP(H)-binding site, in particular regarding those residues that interact with the 2'-phosphate and the pyrophosphate moiety of the coenzyme. The lack of a conserved binding determinant for the 2'-phosphate does not weaken the coenzyme specificity for NADP(H) over NAD(H), which is within the range expected for the diflavin oxidoreductase family of enzymes. Isothermal titration calorimetry reveals a binding constant of 37 and 2 microM for binding of NADP+ and 2',5'-ADP, respectively, for the ligand-protein complex formed with full-length MSR or the isolated FNR module. These values are consistent with Ki values (36 microM for NADP+ and 1.4 microM for 2',5'-ADP) obtained from steady-state inhibition studies. The relatively weaker binding of NADP+ to MSR compared with other members of the diflavin oxidoreductase family might arise from unique electrostatic repulsive forces near the 5'-pyrophosphate moiety and/or increased hydrophobic stacking between Trp697 and the re face of the FAD isoalloxazine ring. Small structural permutations within the NADP(H)-binding cleft have profound affects on coenzyme binding, which likely retards catalytic turnover of the enzyme in the cell. The biological implications of an attenuated mechanism of MS reactivation by MSR on methionine and folate metabolism are discussed.

Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry.,Wolthers KR, Lou X, Toogood HS, Leys D, Scrutton NS Biochemistry. 2007 Oct 23;46(42):11833-44. Epub 2007 Sep 25. PMID:17892308<ref>PMID:17892308</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Leys D]]
[[Category: Lou X]]
[[Category: Scrutton NS]]
[[Category: Toogood HS]]
[[Category: Wolthers KR]]