4pvq: Difference between revisions
New page: {{STRUCTURE_4pvq| PDB=4pvq | SCENE= }} ===Crystal structure of sulfate-bound human l-asparaginase protein=== {{ABSTRACT_PUBMED_22861376}} ==Function== [[http://www.uniprot.org/unipro... |
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== | ==Crystal structure of sulfate-bound human l-asparaginase protein== | ||
[[http://www.uniprot.org/uniprot/ASGL1_HUMAN ASGL1_HUMAN | <StructureSection load='4pvq' size='340' side='right'caption='[[4pvq]], [[Resolution|resolution]] 2.13Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4pvq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4gdu 4gdu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PVQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PVQ 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]] 2.13Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=4pvq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pvq OCA], [https://pdbe.org/4pvq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pvq RCSB], [https://www.ebi.ac.uk/pdbsum/4pvq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pvq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ASGL1_HUMAN ASGL1_HUMAN] Has both L-asparaginase and beta-aspartyl peptidase activity. May be involved in the production of L-aspartate, which can act as an excitatory neurotransmitter in some brain regions. Is highly active with L-Asp beta-methyl ester. Besides, has catalytic activity toward beta-aspartyl dipeptides and their methyl esters, including beta-L-Asp-L-Phe, beta-L-Asp-L-Phe methyl ester (aspartame), beta-L-Asp-L-Ala, beta-L-Asp-L-Leu and beta-L-Asp-L-Lys. Does not have aspartylglucosaminidase activity and is inactive toward GlcNAc-L-Asn. Likewise, has no activity toward glutamine.<ref>PMID:19839645</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Asparaginases catalyze the hydrolysis of the amino acid asparagine to aspartate and ammonia. Bacterial asparaginases are used in cancer chemotherapy to deplete asparagine from the blood, because several hematological malignancies depend on extracellular asparagine for growth. To avoid the immune response against the bacterial enzymes, it would be beneficial to replace them with human asparaginases. However, unlike the bacterial asparaginases, the human enzymes have a millimolar K(m) value for asparagine, making them inefficient in depleting the amino acid from blood. To facilitate the development of human variants suitable for therapeutic use, we determined the structure of human l-asparaginase (hASNase3). This asparaginase is an N-terminal nucleophile (Ntn) family member that requires autocleavage between Gly167 and Thr168 to become catalytically competent. For most Ntn hydrolases, this autoproteolytic activation occurs efficiently. In contrast, hASNas3 is relatively stable in its uncleaved state, and this allowed us to observe the structure of the enzyme prior to cleavage. To determine the structure of the cleaved state, we exploited our discovery that the free amino acid glycine promotes complete cleavage of hASNase3. Both enzyme states were elucidated in the absence and presence of the product aspartate. Together, these structures provide insight into the conformational changes required for cleavage and the precise enzyme-substrate interactions. The new understanding of hASNase3 will serve to guide the design of variants that possess a decreased K(m) value for asparagine, making the human enzyme a suitable replacement for the bacterial asparaginases in cancer therapy. | |||
Structures of Apo and Product-Bound Human l-Asparaginase: Insights into the Mechanism of Autoproteolysis and Substrate Hydrolysis.,Nomme J, Su Y, Konrad M, Lavie A Biochemistry. 2012 Aug 28;51(34):6816-26. Epub 2012 Aug 14. PMID:22861376<ref>PMID:22861376</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
[[ | <div class="pdbe-citations 4pvq" style="background-color:#fffaf0;"></div> | ||
[[Category: | ==See Also== | ||
[[Category: | *[[Asparaginase 3D structures|Asparaginase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Lavie A]] | |||
[[Category: Nomme J]] | |||