8bb7

Crystal structure of Mouse Plexin-B1 (20-535) in complex with VHH15Crystal structure of Mouse Plexin-B1 (20-535) in complex with VHH15

Structural highlights

8bb7 is a 4 chain structure with sequence from Camelidae and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.95Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PLXB1_MOUSE Receptor for SEMA4D (PubMed:19788569). Plays a role in GABAergic synapse development (PubMed:23699507, PubMed:29981480). Mediates SEMA4A- and SEMA4D-dependent inhibitory synapse development (PubMed:23699507, PubMed:29981480). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (By similarity). Plays a role in axon guidance, invasive growth and cell migration (By similarity).[UniProtKB:O43157]^[1] ^[2] ^[3]

Publication Abstract from PubMed

Plexin-B1 is a receptor for the cell surface semaphorin, Sema4D. This signalling system has been implicated in a variety of human diseases, including cancer, multiple sclerosis and osteoporosis. Whilst inhibitors of the Plexin-B1:Sema4D interaction have been previously reported, understanding their mechanism has been hindered by an incomplete structural view of Plexin-B1. In this study, we have raised and characterised a pair of nanobodies that are specific for mouse Plexin-B1, and which inhibit the binding of Sema4D to mouse Plexin-B1 and its biological activity. Structural studies of these nanobodies reveal that they inhibit the binding of Sema4D in an allosteric manner, binding to epitopes not previously reported. In addition, we report the first unbound structure of human Plexin-B1, which reveals that Plexin-B1 undergoes a conformational change on Sema4D binding. These changes mirror those seen upon binding of allosteric peptide modulators, which suggests a new model for understanding Plexin-B1 signalling, and provides a potential innovative route for therapeutic modulation of Plexin-B1.

Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signalling.,Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G J Biol Chem. 2023 Apr 21:104740. doi: 10.1016/j.jbc.2023.104740. PMID:37088134^[4]

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

References

↑ Vodrazka P, Korostylev A, Hirschberg A, Swiercz JM, Worzfeld T, Deng S, Fazzari P, Tamagnone L, Offermanns S, Kuner R. The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. Eur J Neurosci. 2009 Oct;30(7):1193-208. doi: 10.1111/j.1460-9568.2009.06934.x., Epub 2009 Sep 29. PMID:19788569 doi:http://dx.doi.org/10.1111/j.1460-9568.2009.06934.x
↑ Kuzirian MS, Moore AR, Staudenmaier EK, Friedel RH, Paradis S. The class 4 semaphorin Sema4D promotes the rapid assembly of GABAergic synapses in rodent hippocampus. J Neurosci. 2013 May 22;33(21):8961-73. PMID:23699507 doi:10.1523/JNEUROSCI.0989-13.2013
↑ McDermott JE, Goldblatt D, Paradis S. Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus. Mol Cell Neurosci. 2018 Oct;92:50-66. PMID:29981480 doi:10.1016/j.mcn.2018.06.008
↑ Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G. Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signalling. J Biol Chem. 2023 Apr 21:104740. PMID:37088134 doi:10.1016/j.jbc.2023.104740

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OCA

[1] Vodrazka P, Korostylev A, Hirschberg A, Swiercz JM, Worzfeld T, Deng S, Fazzari P, Tamagnone L, Offermanns S, Kuner R. The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. Eur J Neurosci. 2009 Oct;30(7):1193-208. doi: 10.1111/j.1460-9568.2009.06934.x., Epub 2009 Sep 29. PMID:19788569 doi:http://dx.doi.org/10.1111/j.1460-9568.2009.06934.x

[2] Kuzirian MS, Moore AR, Staudenmaier EK, Friedel RH, Paradis S. The class 4 semaphorin Sema4D promotes the rapid assembly of GABAergic synapses in rodent hippocampus. J Neurosci. 2013 May 22;33(21):8961-73. PMID:23699507 doi:10.1523/JNEUROSCI.0989-13.2013

[3] McDermott JE, Goldblatt D, Paradis S. Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus. Mol Cell Neurosci. 2018 Oct;92:50-66. PMID:29981480 doi:10.1016/j.mcn.2018.06.008

[4] Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G. Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signalling. J Biol Chem. 2023 Apr 21:104740. PMID:37088134 doi:10.1016/j.jbc.2023.104740

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