6v7f: Difference between revisions
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==Human Arginase1 Complexed with Bicyclic Inhibitor Compound 13== | ==Human Arginase1 Complexed with Bicyclic Inhibitor Compound 13== | ||
<StructureSection load='6v7f' size='340' side='right'caption='[[6v7f]]' scene=''> | <StructureSection load='6v7f' size='340' side='right'caption='[[6v7f]], [[Resolution|resolution]] 2.02Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V7F OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6v7f]] is a 6 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=6V7F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V7F FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.02Å</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=QRJ:{3-[(5R,7S,8S)-8-azaniumyl-8-carboxy-2-azaspiro[4.4]nonan-2-ium-7-yl]propyl}(trihydroxy)borate(1-)'>QRJ</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=6v7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v7f OCA], [https://pdbe.org/6v7f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v7f RCSB], [https://www.ebi.ac.uk/pdbsum/6v7f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v7f ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored. | |||
Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.,Mitcheltree MJ, Li D, Achab A, Beard A, Chakravarthy K, Cheng M, Cho H, Eangoor P, Fan P, Gathiaka S, Kim HY, Lesburg CA, Lyons TW, Martinot TA, Miller JR, McMinn S, O'Neil J, Palani A, Palte RL, Sauri J, Sloman DL, Zhang H, Cumming JN, Fischer C ACS Med Chem Lett. 2020 Mar 23;11(4):582-588. doi:, 10.1021/acsmedchemlett.0c00058. eCollection 2020 Apr 9. PMID:32292567<ref>PMID:32292567</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6v7f" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Arginase 3D structures|Arginase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lesburg CA]] | [[Category: Lesburg CA]] | ||
[[Category: Palte RL]] | [[Category: Palte RL]] | ||
Latest revision as of 11:05, 11 October 2023
Human Arginase1 Complexed with Bicyclic Inhibitor Compound 13Human Arginase1 Complexed with Bicyclic Inhibitor Compound 13
Structural highlights
DiseaseARGI1_HUMAN Defects in ARG1 are the cause of argininemia (ARGIN) [MIM: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.[1] [2] FunctionPublication Abstract from PubMedThe action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored. Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.,Mitcheltree MJ, Li D, Achab A, Beard A, Chakravarthy K, Cheng M, Cho H, Eangoor P, Fan P, Gathiaka S, Kim HY, Lesburg CA, Lyons TW, Martinot TA, Miller JR, McMinn S, O'Neil J, Palani A, Palte RL, Sauri J, Sloman DL, Zhang H, Cumming JN, Fischer C ACS Med Chem Lett. 2020 Mar 23;11(4):582-588. doi:, 10.1021/acsmedchemlett.0c00058. eCollection 2020 Apr 9. PMID:32292567[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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