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==Human Arginase1 Complexed with Inhibitor Compound 24a== | |||
<StructureSection load='7klm' size='340' side='right'caption='[[7klm]], [[Resolution|resolution]] 2.27Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7klm]] 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=7KLM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KLM 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]] 2.27Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0IZ:3-[(2~{S},3~{R},4~{R})-4-[[(2~{S})-2-azanyl-3-methyl-butanoyl]amino]-2-carboxy-pyrrolidin-3-yl]propyl-$l^{3}-oxidanyl-bis(oxidanyl)boron'>0IZ</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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=7klm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7klm OCA], [https://pdbe.org/7klm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7klm RCSB], [https://www.ebi.ac.uk/pdbsum/7klm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7klm 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 == | |||
Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model. | |||
Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.,Lu M, Zhang H, Li D, Childers M, Pu Q, Palte RL, Gathiaka S, Lyons TW, Palani A, Fan PW, Spacciapoli P, Miller JR, Cho H, Cheng M, Chakravarthy K, O'Neil J, Eangoor P, Beard A, Kim HY, Sauri J, Gunaydin H, Sloman DL, Siliphaivanh P, Cumming J, Fischer C ACS Med Chem Lett. 2021 Jul 16;12(9):1380-1388. doi:, 10.1021/acsmedchemlett.1c00195. eCollection 2021 Sep 9. PMID:34527178<ref>PMID:34527178</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7klm" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Arginase 3D structures|Arginase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Palte RL]] | |||
Latest revision as of 18:27, 18 October 2023
Human Arginase1 Complexed with Inhibitor Compound 24aHuman Arginase1 Complexed with Inhibitor Compound 24a
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 PubMedRecent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model. Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.,Lu M, Zhang H, Li D, Childers M, Pu Q, Palte RL, Gathiaka S, Lyons TW, Palani A, Fan PW, Spacciapoli P, Miller JR, Cho H, Cheng M, Chakravarthy K, O'Neil J, Eangoor P, Beard A, Kim HY, Sauri J, Gunaydin H, Sloman DL, Siliphaivanh P, Cumming J, Fischer C ACS Med Chem Lett. 2021 Jul 16;12(9):1380-1388. doi:, 10.1021/acsmedchemlett.1c00195. eCollection 2021 Sep 9. PMID:34527178[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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