View source for 5nxa


==Crystal structure of Neanderthal Adenylosuccinate Lyase (ADSL)in complex with its products AICAR and fumarate==
<StructureSection load='5nxa' size='340' side='right'caption='[[5nxa]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5nxa]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens_neanderthalensis Homo sapiens neanderthalensis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NXA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NXA 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=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUM:FUMARIC+ACID'>FUM</scene>, <scene name='pdbligand=SSS:N-{[5-AMINO-1-(5-O-PHOSPHONO-BETA-D-ARABINOFURANOSYL)-1H-IMIDAZOL-4-YL]CARBONYL}-L-ASPARTIC+ACID'>SSS</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=5nxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nxa OCA], [https://pdbe.org/5nxa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nxa RCSB], [https://www.ebi.ac.uk/pdbsum/5nxa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nxa ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A384E0N4_HOMNE A0A384E0N4_HOMNE] Catalyzes two non-sequential steps in de novo AMP synthesis: converts (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and thereby also contributes to de novo IMP synthesis, and converts succinyladenosine monophosphate (SAMP) to AMP and fumarate.[ARBA:ARBA00002971]
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== Publication Abstract from PubMed ==
The availability of genomic data from extinct homini such as Neanderthals has caused a revolution in palaeontology allowing the identification of modern human-specific protein substitutions. Currently, little is known as to how these substitutions alter the proteins on a molecular level. Here, we investigate adenylosuccinate lyase, a conserved enzyme involved in purine metabolism for which several substitutions in the modern human protein (hADSL) have been described to affect intelligence and behaviour. During evolution, modern humans acquired a specific substitution (Ala429Val) in ADSL distinguishing it from the ancestral variant present in Neanderthals (nADSL). We show here that despite this conservative substitution being solvent exposed and located distant from the active site, there is a difference in thermal stability, but not enzymology or ligand binding between nADSL and hADSL. Substitutions near residue 429 which do not profoundly affect enzymology were previously reported to cause neurological symptoms in humans. This study also reveals that ADSL undergoes conformational changes during catalysis which, together with the crystal structure of a hitherto undetermined product bound conformation, explains the molecular origin of disease for several modern human ADSL mutants.

Molecular comparison of Neanderthal and Modern Human adenylosuccinate lyase.,Van Laer B, Kapp U, Soler-Lopez M, Moczulska K, Paabo S, Leonard G, Mueller-Dieckmann C Sci Rep. 2018 Dec 20;8(1):18008. doi: 10.1038/s41598-018-36195-5. PMID:30573755<ref>PMID:30573755</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5nxa" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adenylosuccinate lyase 3D structures|Adenylosuccinate lyase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens neanderthalensis]]
[[Category: Large Structures]]
[[Category: Kapp U]]
[[Category: Leonard G]]
[[Category: Mueller-Dieckmann C]]
[[Category: Soler-Lopez M]]
[[Category: Van Laer B]]