| Structural highlights
5b4w is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | NAG |
| NonStd Res: | ACE, DTR, NH2 |
| Gene: | PLXNB1, KIAA0407, PLXN5, SEP (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PLXB1_HUMAN] Receptor for SEMA4D. Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Semaphorin axonal guidance factors are multifunctional proteins that play important roles in immune response, cancer cell proliferation, and organogenesis, making semaphorins and their signaling receptor plexins important drug targets for various diseases. However, the large and flat binding surface of the semaphorin-plexin interaction interface is difficult to target by traditional small-molecule drugs. Here, we report the discovery of a high-affinity plexin B1 (PlxnB1)-binding macrocyclic peptide, PB1m6 (KD = 3.5 nM). PB1m6 specifically inhibited the binding of physiological ligand semaphorin 4D (Sema4D) in vitro and completely suppressed Sema4D-induced cell collapse. Structural studies revealed that PB1m6 binds at a groove between the fifth and sixth blades of the sema domain in PlxnB1 distant from the Sema4D-binding site, indicating the non-competitive and allosteric nature of the inhibitory activity. The discovery of this novel allosteric site can potentially be used to target plexin family proteins for the development of drugs that modulate semaphorin and plexin signaling.
Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide.,Matsunaga Y, Bashiruddin NK, Kitago Y, Takagi J, Suga H Cell Chem Biol. 2016 Nov 17;23(11):1341-1350. doi:, 10.1016/j.chembiol.2016.09.015. Epub 2016 Oct 27. PMID:27984026[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol. 2002 Sep;4(9):720-4. PMID:12198496 doi:10.1038/ncb843
- ↑ Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL. The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12085-90. Epub 2002 Aug 26. PMID:12196628 doi:10.1073/pnas.142433199
- ↑ Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80. PMID:15210733 doi:10.1083/jcb.200312094
- ↑ Tong Y, Hota PK, Penachioni JY, Hamaneh MB, Kim S, Alviani RS, Shen L, He H, Tempel W, Tamagnone L, Park HW, Buck M. Structure and function of the intracellular region of the plexin-b1 transmembrane receptor. J Biol Chem. 2009 Dec 18;284(51):35962-72. Epub . PMID:19843518 doi:10.1074/jbc.M109.056275
- ↑ Janssen BJ, Robinson RA, Perez-Branguli F, Bell CH, Mitchell KJ, Siebold C, Jones EY. Structural basis of semaphorin-plexin signalling. Nature. 2010 Sep 26. PMID:20877282 doi:10.1038/nature09468
- ↑ Bell CH, Aricescu AR, Jones EY, Siebold C. A Dual Binding Mode for RhoGTPases in Plexin Signalling. PLoS Biol. 2011 Aug;9(8):e1001134. Epub 2011 Aug 30. PMID:21912513 doi:10.1371/journal.pbio.1001134
- ↑ Matsunaga Y, Bashiruddin NK, Kitago Y, Takagi J, Suga H. Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide. Cell Chem Biol. 2016 Nov 17;23(11):1341-1350. doi:, 10.1016/j.chembiol.2016.09.015. Epub 2016 Oct 27. PMID:27984026 doi:https://dx.doi.org/10.1016/j.chembiol.2016.09.015
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