View source for 6qaf


==Crystal structure of human Arginase-1 at pH 9.0 in complex with CB-1158/INCB001158==
<StructureSection load='6qaf' size='340' side='right'caption='[[6qaf]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6qaf]] is a 2 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=6QAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QAF 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]] 1.61&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=XC3:[(~{E})-3-[(3~{S},4~{R})-4-azanyl-1-[(2~{S})-2-azanylpropanoyl]-4-carboxy-pyrrolidin-3-yl]prop-1-enyl]-tris(oxidanyl)boranium'>XC3</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=6qaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qaf OCA], [https://pdbe.org/6qaf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qaf RCSB], [https://www.ebi.ac.uk/pdbsum/6qaf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qaf ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:[https://omim.org/entry/207800 207800]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.<ref>PMID:1463019</ref> <ref>PMID:7649538</ref> 
== Function ==
[https://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Arginase-1 is a manganese-dependent metalloenzyme that catalyzes the hydrolysis of L-arginine into L-ornithine and urea. Arginase-1 is abundantly expressed by tumor-infiltrating myeloid cells that promote tumor immunosuppression, which is relieved by inhibition of Arginase-1. We have characterized the potencies of the Arginase-1 reference inhibitors (2S)-2-amino-6-boronohexanoic acid (ABH) and N (omega)-hydroxy-nor-L-arginine (nor-NOHA), and studied their pH-dependence and binding kinetics. To gain a better understanding of the structural changes underlying the high pH optimum of Arginase-1 and its pH-dependent inhibition, we determined the crystal structure of the human Arginase-1/ABH complex at pH 7.0 and 9.0. These structures revealed that at increased pH, the manganese cluster assumes a more symmetrical coordination structure, which presumably contributes to its increase in catalytic activity. Furthermore, we show that binding of ABH involves the presence of a sodium ion close to the manganese cluster. We also studied the investigational new drug CB-1158 (INCB001158). This inhibitor has a low-nanomolar potency at pH 7.4 and increases the thermal stability of Arginase-1 more than ABH and nor-NOHA. Moreover, CB-1158 displays slow association and dissociation kinetics at both pH 9.5 and 7.4, as indicated by surface plasmon resonance. The potent character of CB-1158 is presumably due to its increased rigidity compared to ABH as well as the formation of an additional hydrogen-bond network as observed by resolution of the Arginase-1/CB-1158 crystal structure.

Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158.,Grobben Y, Uitdehaag JCM, Willemsen-Seegers N, Tabak WWA, de Man J, Buijsman RC, Zaman GJR J Struct Biol X. 2019 Nov 26;4:100014. doi: 10.1016/j.yjsbx.2019.100014., eCollection 2020. PMID:32647818<ref>PMID:32647818</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6qaf" style="background-color:#fffaf0;"></div>

==See Also==
*[[Arginase 3D structures|Arginase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Grobben Y]]
[[Category: Tabak WWA]]
[[Category: Uitdehaag JCM]]
[[Category: Zaman GJR]]