4m6l: Difference between revisions

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-{{STRUCTURE_4m6l|  PDB=4m6l  |  SCENE=  }}
-===Crystal structure of human dihydrofolate reductase (DHFR) bound to NADP+ and 5,10-dideazatetrahydrofolic acid===
-==Disease==
+==Crystal structure of human dihydrofolate reductase (DHFR) bound to NADP+ and 5,10-dideazatetrahydrofolic acid==
-[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[http://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
+<StructureSection load='4m6l' size='340' side='right'caption='[[4m6l]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4m6l]] 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=4M6L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M6L 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]] 1.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=21V:N-(4-{2-[(6S)-2-AMINO-4-OXO-1,4,5,6,7,8-HEXAHYDROPYRIDO[2,3-D]PYRIMIDIN-6-YL]ETHYL}BENZOYL)-L-GLUTAMIC+ACID'>21V</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4m6l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m6l OCA], [https://pdbe.org/4m6l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m6l RCSB], [https://www.ebi.ac.uk/pdbsum/4m6l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m6l ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Molecular evolution is driven by mutations, which may affect the fitness of an organism and are then subject to natural selection or genetic drift. Analysis of primary protein sequences and tertiary structures has yielded valuable insights into the evolution of protein function, but little is known about the evolution of functional mechanisms, protein dynamics and conformational plasticity essential for activity. We characterized the atomic-level motions across divergent members of the dihydrofolate reductase (DHFR) family. Despite structural similarity, Escherichia coli and human DHFRs use different dynamic mechanisms to perform the same function, and human DHFR cannot complement DHFR-deficient E. coli cells. Identification of the primary-sequence determinants of flexibility in DHFRs from several species allowed us to propose a likely scenario for the evolution of functionally important DHFR dynamics following a pattern of divergent evolution that is tuned by cellular environment.
-==Function==
+Divergent evolution of protein conformational dynamics in dihydrofolate reductase.,Bhabha G, Ekiert DC, Jennewein M, Zmasek CM, Tuttle LM, Kroon G, Dyson HJ, Godzik A, Wilson IA, Wright PE Nat Struct Mol Biol. 2013 Sep 29. doi: 10.1038/nsmb.2676. PMID:24077226<ref>PMID:24077226</ref>
-[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[4m6l]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M6L OCA].
+</div>
+<div class="pdbe-citations 4m6l" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-<references group="xtra"/><references/>
+*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
-[[Category: Dihydrofolate reductase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Bhabha, G.]]
+[[Category: Large Structures]]
-[[Category: Ekiert, D C.]]
+[[Category: Bhabha G]]
-[[Category: Wilson, I A.]]
+[[Category: Ekiert DC]]
-[[Category: Wright, P E.]]
+[[Category: Wilson IA]]
-[[Category: Folate binding]]
+[[Category: Wright PE]]
-[[Category: Nadph binding]]
-[[Category: Oxidoreductase]]
-[[Category: Rossmann fold]]