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4lxd

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Revision as of 12:37, 11 August 2016

Bcl_2-Navitoclax Analog (without Thiophenyl) Complex

Structural highlights

4lxd is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4lvt, 4lxe
Gene:	BCL2 (HUMAN)
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

[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).^[1]

Publication Abstract from PubMed

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.,Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW Nat Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048. Epub 2013 Jan 6. PMID:23291630^[2]

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

References

↑ 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
↑ Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048. Epub 2013 Jan 6. PMID:23291630 doi:10.1038/nm.3048

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4lxd"

Categories: Human | Park, C H | Helice | Apoptosis regulator-inhibitor complex

@@ Line 1: / Line 1: @@
 ==Bcl_2-Navitoclax Analog (without Thiophenyl) Complex==
 <StructureSection load='4lxd' size='340' side='right' caption='[[4lxd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4lxd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ochroconis_lascauxensis Ochroconis lascauxensis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LXD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LXD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4lxd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LXD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LXD FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1XV:4-(4-{[4-(4-CHLOROPHENYL)-5,6-DIHYDRO-2H-PYRAN-3-YL]METHYL}PIPERAZIN-1-YL)-N-{[3-NITRO-4-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)PHENYL]SULFONYL}BENZAMIDE'>1XV</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lvt|4lvt]], [[4lxe|4lxe]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=994323 Ochroconis lascauxensis])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4lxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lxd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lxd RCSB], [http://www.ebi.ac.uk/pdbsum/4lxd PDBsum]</span></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=4lxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lxd OCA], [http://pdbe.org/4lxd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lxd RCSB], [http://www.ebi.ac.uk/pdbsum/4lxd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lxd ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4lxd" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 27: / Line 29: @@
 __TOC__
 </StructureSection>
-[[Category: Ochroconis lascauxensis]]
+[[Category: Human]]
 [[Category: Park, C H]]
 [[Category: Helice]]
 [[Category: Apoptosis regulator-inhibitor complex]]

4lxd

From Proteopedia

Revision as of 12:37, 11 August 2016

Bcl_2-Navitoclax Analog (without Thiophenyl) Complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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