View source for 6gq3


==Human asparagine synthetase (ASNS) in complex with 6-diazo-5-oxo-L-norleucine (DON) at 1.85 A resolution==
<StructureSection load='6gq3' size='340' side='right'caption='[[6gq3]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6gq3]] 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=6GQ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GQ3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=ONL:5-OXO-L-NORLEUCINE'>ONL</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ASNS, TS11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Asparagine_synthase_(glutamine-hydrolyzing) Asparagine synthase (glutamine-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.5.4 6.3.5.4] </span></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=6gq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gq3 OCA], [http://pdbe.org/6gq3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gq3 RCSB], [http://www.ebi.ac.uk/pdbsum/6gq3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gq3 ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/ASNS_HUMAN ASNS_HUMAN]] Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome. The disease is caused by mutations affecting the gene represented in this entry. 
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== Publication Abstract from PubMed ==
Expression of human asparagine synthetase (ASNS) promotes metastatic progression and tumor cell invasiveness in colorectal and breast cancer, presumably by altering cellular levels of L-asparagine. Human ASNS is therefore emerging as a bona fide drug target for cancer therapy. Here we show that a slow-onset, tight binding inhibitor, which exhibits nanomolar affinity for human ASNS in vitro, exhibits excellent selectivity at 10 muM concentration in HCT-116 cell lysates with almost no off-target binding. The high-resolution (1.85 A) crystal structure of human ASNS has enabled us to identify a cluster of negatively charged side chains in the synthetase domain that plays a key role in inhibitor binding. Comparing this structure with those of evolutionarily related AMP-forming enzymes provides insights into intermolecular interactions that give rise to the observed binding selectivity. Our findings demonstrate the feasibility of developing second generation human ASNS inhibitors as lead compounds for the discovery of drugs against metastasis.

High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity.,Zhu W, Radadiya A, Bisson C, Wenzel S, Nordin BE, Martinez-Marquez F, Imasaki T, Sedelnikova SE, Coricello A, Baumann P, Berry AH, Nomanbhoy TK, Kozarich JW, Jin Y, Rice DW, Takagi Y, Richards NGJ Commun Biol. 2019 Sep 17;2:345. doi: 10.1038/s42003-019-0587-z. eCollection 2019. PMID:31552298<ref>PMID:31552298</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6gq3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Berry, A H]]
[[Category: Bisson, C]]
[[Category: Imasaki, T]]
[[Category: Jin, Y]]
[[Category: Kozarich, J W]]
[[Category: Nomanbhoy, T K]]
[[Category: Nordin, B E]]
[[Category: Radadiya, A]]
[[Category: Rice, D W]]
[[Category: Richards, N G.J]]
[[Category: Sedelnikova, S E]]
[[Category: Takagi, Y]]
[[Category: Wenzel, S]]
[[Category: Zhu, W]]
[[Category: Biosynthetic protein]]
[[Category: Breast cancer]]
[[Category: Inhibitor development]]
[[Category: L-asparagine biosynthesis]]