|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6ss6' size='340' side='right'caption='[[6ss6]], [[Resolution|resolution]] 3.25Å' scene=''> | | <StructureSection load='6ss6' size='340' side='right'caption='[[6ss6]], [[Resolution|resolution]] 3.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ss6]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SS6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6SS6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ss6]] is a 9 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=6SS6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SS6 FirstGlance]. <br> |
| - | </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=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6srv|6srv]], [[6srx|6srx]], [[6ss0|6ss0]], [[6ss2|6ss2]], [[6ss4|6ss4]], [[6ss5|6ss5]], [[6tul|6tul]]</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=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ss6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ss6 OCA], [https://pdbe.org/6ss6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ss6 RCSB], [https://www.ebi.ac.uk/pdbsum/6ss6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ss6 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Arginase Arginase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.1 3.5.3.1] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ss6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ss6 OCA], [http://pdbe.org/6ss6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ss6 RCSB], [http://www.ebi.ac.uk/pdbsum/6ss6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ss6 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6ss6" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6ss6" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Arginase 3D structures|Arginase 3D structures]] |
| | + | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Arginase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Addyman, A]] | + | [[Category: Addyman A]] |
| - | [[Category: Burschowsky, D]] | + | [[Category: Burschowsky D]] |
| - | [[Category: Carr, M]] | + | [[Category: Carr M]] |
| - | [[Category: Fiedler, S]] | + | [[Category: Fiedler S]] |
| - | [[Category: Groves, M]] | + | [[Category: Groves M]] |
| - | [[Category: Haynes, S]] | + | [[Category: Haynes S]] |
| - | [[Category: Seewooruthun, C]] | + | [[Category: Seewooruthun C]] |
| - | [[Category: Antigen-binding fragment]]
| + | |
| - | [[Category: Arginase-2 inhibitor]]
| + | |
| - | [[Category: Igg]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| Structural highlights
Function
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.
Publication Abstract from PubMed
Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time. In this study, we used a method that combined antibody chain shuffling and a staggered-extension process to produce unbiased libraries, which recombined beneficial mutations from all six complementarity-determining regions (CDRs) in the affinity maturation of an inhibitory antibody to Arginase 2 (ARG2). We made use of the vast display capacity of ribosome display to accommodate the sequence space required for the diverse library builds. Further diversity was introduced through pool maturation to optimize seven leads of interest simultaneously. This resulted in antibodies with substantial improvements in binding properties and inhibition potency. The extensive sequence changes resulting from this approach were translated into striking structural changes for parent and affinity-matured antibodies bound to ARG2, with a large reorientation of the binding paratope facilitating increases in contact surface and shape complementarity to the antigen. The considerable gains in therapeutic properties seen from extensive sequence and structural evolution of the parent ARG2 inhibitory antibody clearly illustrate the advantages of the unbiased approach developed, which was key to the identification of high-affinity antibodies with the desired inhibitory potency and specificity.
Extensive sequence and structural evolution of Arginase 2 inhibitory antibodies enabled by an unbiased approach to affinity maturation.,Chan DTY, Jenkinson L, Haynes SW, Austin M, Diamandakis A, Burschowsky D, Seewooruthun C, Addyman A, Fiedler S, Ryman S, Whitehouse J, Slater LH, Gowans E, Shibata Y, Barnard M, Wilkinson RW, Vaughan TJ, Holt SV, Cerundolo V, Carr MD, Groves MAT Proc Natl Acad Sci U S A. 2020 Jul 2. pii: 1919565117. doi:, 10.1073/pnas.1919565117. PMID:32616569[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chan DTY, Jenkinson L, Haynes SW, Austin M, Diamandakis A, Burschowsky D, Seewooruthun C, Addyman A, Fiedler S, Ryman S, Whitehouse J, Slater LH, Gowans E, Shibata Y, Barnard M, Wilkinson RW, Vaughan TJ, Holt SV, Cerundolo V, Carr MD, Groves MAT. Extensive sequence and structural evolution of Arginase 2 inhibitory antibodies enabled by an unbiased approach to affinity maturation. Proc Natl Acad Sci U S A. 2020 Jul 2. pii: 1919565117. doi:, 10.1073/pnas.1919565117. PMID:32616569 doi:http://dx.doi.org/10.1073/pnas.1919565117
|
