5c3g

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of Bcl-xl bound to BIM-MM

Structural highlights

5c3g is a 2 chain structure with sequence from Homo sapiens 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 2.45Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

B2L11_HUMAN Induces apoptosis and anoikis. Isoform BimL is more potent than isoform BimEL. Isoform Bim-alpha1, isoform Bim-alpha2 and isoform Bim-alpha3 induce apoptosis, although less potent than isoform BimEL, isoform BimL and isoform BimS. Isoform Bim-gamma induces apoptosis. Isoform Bim-alpha3 induces apoptosis possibly through a caspase-mediated pathway. Isoform BimAC and isoform BimABC lack the ability to induce apoptosis.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel alpha-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive alpha-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-xL and Mcl-1 PPIs. SPR analyses indicate binding occurs via an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy-entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein-protein interactions.

Hydrocarbon constrained peptides - understanding preorganisation and binding affinity.,Miles JA, Yeo DJ, Rowell P, Rodriguez-Marin S, Pask CM, Warriner SL, Edwards TA, Wilson AJ Chem Sci. 2016 Jun 1;7(6):3694-3702. doi: 10.1039/c5sc04048e. Epub 2016 Feb 29. PMID:28970875^[7]

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

References

↑ O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 1998 Jan 15;17(2):384-95. PMID:9430630 doi:http://dx.doi.org/10.1093/emboj/17.2.384
↑ U M, Miyashita T, Shikama Y, Tadokoro K, Yamada M. Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family. FEBS Lett. 2001 Nov 30;509(1):135-41. PMID:11734221
↑ Liu JW, Chandra D, Tang SH, Chopra D, Tang DG. Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim. Cancer Res. 2002 May 15;62(10):2976-81. PMID:12019181
↑ Marani M, Tenev T, Hancock D, Downward J, Lemoine NR. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol. 2002 Jun;22(11):3577-89. PMID:11997495
↑ Chen JZ, Ji CN, Gu SH, Li JX, Zhao EP, Huang Y, Huang L, Ying K, Xie Y, Mao YM. Over-expression of Bim alpha3, a novel isoform of human Bim, result in cell apoptosis. Int J Biochem Cell Biol. 2004 Aug;36(8):1554-61. PMID:15147734 doi:http://dx.doi.org/10.1016/j.biocel.2003.12.015
↑ Fukazawa H, Noguchi K, Masumi A, Murakami Y, Uehara Y. BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors. Mol Cancer Ther. 2004 Oct;3(10):1281-8. PMID:15486195
↑ Miles JA, Yeo DJ, Rowell P, Rodriguez-Marin S, Pask CM, Warriner SL, Edwards TA, Wilson AJ. Hydrocarbon constrained peptides - understanding preorganisation and binding affinity. Chem Sci. 2016 Jun 1;7(6):3694-3702. doi: 10.1039/c5sc04048e. Epub 2016 Feb 29. PMID:28970875 doi:http://dx.doi.org/10.1039/c5sc04048e

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5c3g"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5c3g is ON HOLD  until Paper Publication
+==Crystal structure of Bcl-xl bound to BIM-MM==
+<StructureSection load='5c3g' size='340' side='right'caption='[[5c3g]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5c3g]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5C3G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C3G 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]] 2.45&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></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=5c3g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c3g OCA], [https://pdbe.org/5c3g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c3g RCSB], [https://www.ebi.ac.uk/pdbsum/5c3g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c3g ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/B2L11_HUMAN B2L11_HUMAN] Induces apoptosis and anoikis. Isoform BimL is more potent than isoform BimEL. Isoform Bim-alpha1, isoform Bim-alpha2 and isoform Bim-alpha3 induce apoptosis, although less potent than isoform BimEL, isoform BimL and isoform BimS. Isoform Bim-gamma induces apoptosis. Isoform Bim-alpha3 induces apoptosis possibly through a caspase-mediated pathway. Isoform BimAC and isoform BimABC lack the ability to induce apoptosis.<ref>PMID:9430630</ref> <ref>PMID:11734221</ref> <ref>PMID:12019181</ref> <ref>PMID:11997495</ref> <ref>PMID:15147734</ref> <ref>PMID:15486195</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel alpha-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive alpha-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-xL and Mcl-1 PPIs. SPR analyses indicate binding occurs via an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy-entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein-protein interactions.
-Authors: Miles, J.A., Yeo, D.J., Rowell, P., Rodriguez-Marin, S., Pask, C.M., Warriner, S.L., Edwards, T.A., Wilson, A.J.
+Hydrocarbon constrained peptides - understanding preorganisation and binding affinity.,Miles JA, Yeo DJ, Rowell P, Rodriguez-Marin S, Pask CM, Warriner SL, Edwards TA, Wilson AJ Chem Sci. 2016 Jun 1;7(6):3694-3702. doi: 10.1039/c5sc04048e. Epub 2016 Feb 29. PMID:28970875<ref>PMID:28970875</ref>
-Description: Crystal structure of Bcl-xl bound to BIM-MM
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Yeo, D.J]]
+<div class="pdbe-citations 5c3g" style="background-color:#fffaf0;"></div>
-[[Category: Rowell, P]]
-[[Category: Warriner, S.L]]
+==See Also==
-[[Category: Edwards, T.A]]
+*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
-[[Category: Wilson, A.J]]
+== References ==
-[[Category: Pask, C.M]]
+<references/>
-[[Category: Rodriguez-Marin, S]]
+__TOC__
-[[Category: Miles, J.A]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Edwards TA]]
+[[Category: Miles JA]]
+[[Category: Pask CM]]
+[[Category: Rodriguez-Marin S]]
+[[Category: Rowell P]]
+[[Category: Warriner SL]]
+[[Category: Wilson AJ]]
+[[Category: Yeo DJ]]

5c3g

From Proteopedia

Current revision

Crystal structure of Bcl-xl bound to BIM-MM

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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