6o0l

From Proteopedia

(Difference between revisions)

Current revision

crystal structure of BCL-2 G101V mutation with venetoclax

Structural highlights

6o0l is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BCL2_HUMAN Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.

Function

B2CL1_HUMAN Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.^[1] ^[2] Isoform Bcl-X(S) promotes apoptosis.^[3] ^[4] BCL2_HUMAN Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).^[5]

Publication Abstract from PubMed

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations.,Birkinshaw RW, Gong JN, Luo CS, Lio D, White CA, Anderson MA, Blombery P, Lessene G, Majewski IJ, Thijssen R, Roberts AW, Huang DCS, Colman PM, Czabotar PE Nat Commun. 2019 Jun 3;10(1):2385. doi: 10.1038/s41467-019-10363-1. PMID:31160589^[6]

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

References

↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
↑ Birkinshaw RW, Gong JN, Luo CS, Lio D, White CA, Anderson MA, Blombery P, Lessene G, Majewski IJ, Thijssen R, Roberts AW, Huang DCS, Colman PM, Czabotar PE. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun. 2019 Jun 3;10(1):2385. doi: 10.1038/s41467-019-10363-1. PMID:31160589 doi:http://dx.doi.org/10.1038/s41467-019-10363-1

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/6o0l"

@@ Line 3: / Line 3: @@
 <StructureSection load='6o0l' size='340' side='right'caption='[[6o0l]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6o0l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O0L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O0L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6o0l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O0L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O0L FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=LBM:4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-~{N}-[4-(oxan-4-ylmethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]sulfonyl-2-(1~{H}-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide'>LBM</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.2&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o0l OCA], [http://pdbe.org/6o0l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o0l RCSB], [http://www.ebi.ac.uk/pdbsum/6o0l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o0l ProSAT]</span></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=LBM:4-{4-[(4-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(oxan-4-yl+)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide'>LBM</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=6o0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o0l OCA], [https://pdbe.org/6o0l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o0l RCSB], [https://www.ebi.ac.uk/pdbsum/6o0l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o0l ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
+== Function ==
+[https://www.uniprot.org/uniprot/B2CL1_HUMAN B2CL1_HUMAN] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref>   Isoform Bcl-X(S) promotes apoptosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> [https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).<ref>PMID:18570871</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.
+Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations.,Birkinshaw RW, Gong JN, Luo CS, Lio D, White CA, Anderson MA, Blombery P, Lessene G, Majewski IJ, Thijssen R, Roberts AW, Huang DCS, Colman PM, Czabotar PE Nat Commun. 2019 Jun 3;10(1):2385. doi: 10.1038/s41467-019-10363-1. PMID:31160589<ref>PMID:31160589</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6o0l" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Birkinshaw, R W]]
+[[Category: Birkinshaw RW]]
-[[Category: Colman, P M]]
+[[Category: Colman PM]]
-[[Category: Czabotar, P E]]
+[[Category: Czabotar PE]]
-[[Category: Luo, C S]]
+[[Category: Luo CS]]
-[[Category: Apoptosis]]
-[[Category: Bcl-2]]
-[[Category: Complex]]
-[[Category: Fda approved drug complex]]
-[[Category: Protein-protein interface inhibitor]]
-[[Category: Resistance mutation]]
-[[Category: Venetoclax]]

6o0l

From Proteopedia

Current revision

crystal structure of BCL-2 G101V mutation with venetoclax

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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