View source for 6ss4


==Structure of arginase-2 in complex with the inhibitory human antigen-binding fragment Fab C0021181==
<StructureSection load='6ss4' size='340' side='right'caption='[[6ss4]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ss4]] is a 3 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=6SS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SS4 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]] 2.9&#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=PO4:PHOSPHATE+ION'>PO4</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=6ss4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ss4 OCA], [https://pdbe.org/6ss4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ss4 RCSB], [https://www.ebi.ac.uk/pdbsum/6ss4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ss4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ARGI2_HUMAN ARGI2_HUMAN] May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to NO synthase. Since NO synthase is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase II plays a role in both male and female sexual arousal. It is therefore a potential target for the treatment of male and female sexual arousal disorders.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses. Here we describe the isolation and characterization of a high affinity antibody (C0021158) that inhibits ARG2 enzymatic function completely, effectively restoring T-cell proliferation in vitro. Enzyme kinetic studies confirmed that C0021158 exhibits a noncompetitive mechanism of action, inhibiting ARG2 independently of L-arginine concentrations. To elucidate C0021158's inhibitory mechanism at a structural level, the co-crystal structure of the Fab in complex with trimeric ARG2 was solved. C0021158's epitope was consequently mapped to an area some distance from the enzyme's substrate binding cleft, indicating an allosteric mechanism was being employed. Following C0021158 binding, distinct regions of ARG2 undergo major conformational changes. Notably, the backbone structure of a surface-exposed loop is completely rearranged, leading to the formation of a new short helix structure at the Fab-ARG2 interface. Moreover, this large-scale structural remodeling at ARG2's epitope translates into more subtle changes within the enzyme's active site. An arginine residue at position 39 is reoriented inwards, sterically impeding the binding of L-arginine. Arg39 is also predicted to alter the pK A of a key catalytic histidine residue at position 160, further attenuating ARG2's enzymatic function. In silico molecular docking simulations predict that L-arginine is unable to bind effectively when antibody is bound, a prediction supported by isothermal calorimetry experiments using an L-arginine mimetic. Specifically, targeting ARG2 in the tumor microenvironment through the application of C0021158, potentially in combination with standard chemotherapy regimens or alternate immunotherapies, represents a potential new strategy to target immune cold tumors.

Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.,Austin M, Burschowsky D, Chan DTY, Jenkinson L, Haynes S, Diamandakis A, Seewooruthun C, Addyman A, Fiedler S, Ryman S, Whitehouse J, Slater LH, Hadjinicolaou AV, Gileadi U, Gowans E, Shibata Y, Barnard M, Kaserer T, Sharma P, Luheshi NM, Wilkinson RW, Vaughan TJ, Holt SV, Cerundolo V, Carr MD, Groves MAT MAbs. 2020 Jan-Dec;12(1):1801230. doi: 10.1080/19420862.2020.1801230. PMID:32880207<ref>PMID:32880207</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ss4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Arginase 3D structures|Arginase 3D structures]]
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Addyman A]]
[[Category: Burschowsky D]]
[[Category: Carr M]]
[[Category: Fiedler S]]
[[Category: Groves M]]
[[Category: Haynes S]]
[[Category: Seewooruthun C]]