7ud4: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7ud4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Adeno-associated_virus Adeno-associated virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UD4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ud4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Adeno-associated_virus Adeno-associated virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UD4 FirstGlance]. <br> | ||
</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=7ud4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ud4 OCA], [https://pdbe.org/7ud4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ud4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ud4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ud4 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.24Å</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=7ud4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ud4 OCA], [https://pdbe.org/7ud4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ud4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ud4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ud4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/Q6JC40_9VIRU Q6JC40_9VIRU] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Adeno-associated virus serotype 9 (AAV9) is a promising gene therapy vector for treating neurodegenerative diseases due to its ability to penetrate the blood-brain barrier. PHP.eB was engineered from AAV9 by insertion of a 7-amino acid peptide and point mutation of neighboring residues, thereby enhancing potency in the central nervous system. Here, we report a 2.24-A resolution cryo-electron microscopy structure of PHP.eB, revealing conformational differences from other 7-mer insertion capsid variants. In PHP.eB, the 7-mer loop adopts a bent conformation, mediated by an interaction between engineered lysine and aspartate residues. Further, we identify PKD2 as the main AAV receptor (AAVR) domain recognizing both AAV9 and PHP.eB and find that the PHP.eB 7-mer partially destabilizes this interaction. Analysis of previously reported AAV structures together with our pull-down data demonstrate that the 7-mer topology determined by the lysine-aspartate interaction dictates AAVR binding strength. Our results suggest that PHP.eB's altered tropism may arise from both an additional interaction with LY6A and weakening of its AAVR interaction. Changing the insertion length, but not sequence, modifies PKD2 binding affinity, suggesting that a steric clash impedes AAVR binding. This research suggests improved library designs for future AAV selections to identify non-LY6A-dependent vectors and modulate AAVR interaction strength. | Adeno-associated virus serotype 9 (AAV9) is a promising gene therapy vector for treating neurodegenerative diseases due to its ability to penetrate the blood-brain barrier. PHP.eB was engineered from AAV9 by insertion of a 7-amino acid peptide and point mutation of neighboring residues, thereby enhancing potency in the central nervous system. Here, we report a 2.24-A resolution cryo-electron microscopy structure of PHP.eB, revealing conformational differences from other 7-mer insertion capsid variants. In PHP.eB, the 7-mer loop adopts a bent conformation, mediated by an interaction between engineered lysine and aspartate residues. Further, we identify PKD2 as the main AAV receptor (AAVR) domain recognizing both AAV9 and PHP.eB and find that the PHP.eB 7-mer partially destabilizes this interaction. Analysis of previously reported AAV structures together with our pull-down data demonstrate that the 7-mer topology determined by the lysine-aspartate interaction dictates AAVR binding strength. Our results suggest that PHP.eB's altered tropism may arise from both an additional interaction with LY6A and weakening of its AAVR interaction. Changing the insertion length, but not sequence, modifies PKD2 binding affinity, suggesting that a steric clash impedes AAVR binding. This research suggests improved library designs for future AAV selections to identify non-LY6A-dependent vectors and modulate AAVR interaction strength. | ||
Structural basis of receptor usage by the engineered capsid AAV-PHP.eB.,Jang S, Shen HK, Ding X, Miles TF, Gradinaru V Mol Ther Methods Clin Dev. 2022 Jul 31;26:343-354. doi:, 10.1016/j.omtm.2022.07.011. eCollection 2022 Sep 8. PMID:36034770<ref>PMID:36034770</ref> | Structural basis of receptor usage by the engineered capsid AAV-PHP.eB.,Jang S, Shen HK, Ding X, Miles TF, Gradinaru V Mol Ther Methods Clin Dev. 2022 Jul 31;26:343-354. doi: , 10.1016/j.omtm.2022.07.011. eCollection 2022 Sep 8. PMID:36034770<ref>PMID:36034770</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||