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4bpj

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Mcl-1 bound to alpha beta Puma BH3 peptide 3

Structural highlights

4bpj 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 1.599Å
Ligands:	, , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MCL1_MOUSE Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis.MCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.^[1]

Publication Abstract from PubMed

We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported alpha/beta-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived alpha/beta-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three alpha residues of the original alpha/beta backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new alpha/beta-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.

Structure-guided rational design of alpha/beta-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.,Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD Chembiochem. 2013 Sep 2;14(13):1564-72. doi: 10.1002/cbic.201300351. Epub 2013, Aug 8. PMID:23929624^[2]

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

References

↑ Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000 Jul 21;275(29):22136-46. PMID:10766760 doi:10.1074/jbc.M909572199
↑ Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD. Structure-guided rational design of alpha/beta-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. Chembiochem. 2013 Sep 2;14(13):1564-72. doi: 10.1002/cbic.201300351. Epub 2013, Aug 8. PMID:23929624 doi:http://dx.doi.org/10.1002/cbic.201300351

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/4bpj"

@@ Line 3: / Line 3: @@
 <StructureSection load='4bpj' size='340' side='right'caption='[[4bpj]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4bpj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BPJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4bpj]] 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=4BPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BPJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.599&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=B3A:(3S)-3-AMINOBUTANOIC+ACID'>B3A</scene>, <scene name='pdbligand=B3D:3-AMINOPENTANEDIOIC+ACID'>B3D</scene>, <scene name='pdbligand=B3Q:(3S)-3,6-DIAMINO-6-OXOHEXANOIC+ACID'>B3Q</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=HR7:(3S)-3-AMINO-6-[(DIAMINOMETHYLIDENE)AMINO]HEXANOIC+ACID'>HR7</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B3A:(3S)-3-AMINOBUTANOIC+ACID'>B3A</scene>, <scene name='pdbligand=B3D:3-AMINOPENTANEDIOIC+ACID'>B3D</scene>, <scene name='pdbligand=B3Q:(3S)-3,6-DIAMINO-6-OXOHEXANOIC+ACID'>B3Q</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=HR7:(3S)-3-AMINO-6-[(DIAMINOMETHYLIDENE)AMINO]HEXANOIC+ACID'>HR7</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4bpi|4bpi]], [[4bpk|4bpk]]</div></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=4bpj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bpj OCA], [https://pdbe.org/4bpj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bpj RCSB], [https://www.ebi.ac.uk/pdbsum/4bpj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bpj ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/MCL1_MOUSE MCL1_MOUSE]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis.
+[https://www.uniprot.org/uniprot/MCL1_MOUSE MCL1_MOUSE] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis.[https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Checco, J W]]
+[[Category: Mus musculus]]
-[[Category: Fairlie, W D]]
+[[Category: Checco JW]]
-[[Category: Gellman, S H]]
+[[Category: Fairlie WD]]
-[[Category: Lee, E F]]
+[[Category: Gellman SH]]
-[[Category: Smith, B J]]
+[[Category: Lee EF]]
-[[Category: Apoptosis]]
+[[Category: Smith BJ]]
-[[Category: Bim]]
-[[Category: Chimera]]

4bpj

From Proteopedia

Current revision

Mcl-1 bound to alpha beta Puma BH3 peptide 3

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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