8hxq

From Proteopedia

(Difference between revisions)

Current revision

Nanobody1 in complex with human BCMA ECD

Structural highlights

8hxq is a 4 chain structure with sequence from Homo sapiens and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TNR17_HUMAN Note=A chromosomal aberration involving TNFRSF17 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with IL2.

Function

TNR17_HUMAN Receptor for TNFSF13B/BLyS/BAFF and TNFSF13/APRIL. Promotes B-cell survival and plays a role in the regulation of humoral immunity. Activates NF-kappa-B and JNK.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.,Sun Y, Yang XN, Yang SS, Lyu YZ, Zhang B, Liu KW, Li N, Cui JC, Huang GX, Liu CL, Xu J, Mi JQ, Chen Z, Fan XH, Chen SJ, Chen S Signal Transduct Target Ther. 2023 Dec 8;8(1):445. doi: , 10.1038/s41392-023-01686-z. PMID:38062078^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hatzoglou A, Roussel J, Bourgeade MF, Rogier E, Madry C, Inoue J, Devergne O, Tsapis A. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol. 2000 Aug 1;165(3):1322-30. PMID:10903733
↑ Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000 Apr 27;404(6781):995-9. PMID:10801128 doi:10.1038/35010115
↑ Yu G, Boone T, Delaney J, Hawkins N, Kelley M, Ramakrishnan M, McCabe S, Qiu WR, Kornuc M, Xia XZ, Guo J, Stolina M, Boyle WJ, Sarosi I, Hsu H, Senaldi G, Theill LE. APRIL and TALL-I and receptors BCMA and TACI: system for regulating humoral immunity. Nat Immunol. 2000 Sep;1(3):252-6. PMID:10973284 doi:10.1038/79802
↑ Sun Y, Yang XN, Yang SS, Lyu YZ, Zhang B, Liu KW, Li N, Cui JC, Huang GX, Liu CL, Xu J, Mi JQ, Chen Z, Fan XH, Chen SJ, Chen S. Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity. Signal Transduct Target Ther. 2023 Dec 8;8(1):445. PMID:38062078 doi:10.1038/s41392-023-01686-z

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8hxq"

Categories: Homo sapiens | Large Structures | Vicugna pacos | Sun Y | Zhang B

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8hxq is ON HOLD
+==Nanobody1 in complex with human BCMA ECD==
+<StructureSection load='8hxq' size='340' side='right'caption='[[8hxq]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8hxq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Vicugna_pacos Vicugna pacos]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HXQ 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]] 2.4&#8491;</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=8hxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hxq OCA], [https://pdbe.org/8hxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hxq RCSB], [https://www.ebi.ac.uk/pdbsum/8hxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hxq ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/TNR17_HUMAN TNR17_HUMAN] Note=A chromosomal aberration involving TNFRSF17 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with IL2.
+== Function ==
+[https://www.uniprot.org/uniprot/TNR17_HUMAN TNR17_HUMAN] Receptor for TNFSF13B/BLyS/BAFF and TNFSF13/APRIL. Promotes B-cell survival and plays a role in the regulation of humoral immunity. Activates NF-kappa-B and JNK.<ref>PMID:10903733</ref> <ref>PMID:10801128</ref> <ref>PMID:10973284</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.
-Authors: Yan, S., Bing, Z.
+Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.,Sun Y, Yang XN, Yang SS, Lyu YZ, Zhang B, Liu KW, Li N, Cui JC, Huang GX, Liu CL, Xu J, Mi JQ, Chen Z, Fan XH, Chen SJ, Chen S Signal Transduct Target Ther. 2023 Dec 8;8(1):445. doi: , 10.1038/s41392-023-01686-z. PMID:38062078<ref>PMID:38062078</ref>
-Description: Nanobody1 in complex with human BCMA ECD
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Bing, Z]]
+<div class="pdbe-citations 8hxq" style="background-color:#fffaf0;"></div>
-[[Category: Yan, S]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Vicugna pacos]]
+[[Category: Sun Y]]
+[[Category: Zhang B]]

8hxq

From Proteopedia

Current revision

Nanobody1 in complex with human BCMA ECD

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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