| Structural highlights
5uul is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| NonStd Res: | , |
| Related: | 5uuk, 5uum, 5uup |
| Gene: | BCL2A1, BCL2L5, BFL1, GRS, HBPA1 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[B2LA1_HUMAN] Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). [BBC3_HUMAN] Essential mediator of p53/TP53-dependent and p53/TP53-independent apoptosis. Functions by promoting partial unfolding of BCL2L1 and dissociation of BCL2L1 from p53/TP53. Regulates ER stress-induced neuronal apoptosis.[1] [2]
Publication Abstract from PubMed
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.
Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1.,Jenson JM, Ryan JA, Grant RA, Letai A, Keating AE Elife. 2017 Jun 8;6. pii: e25541. doi: 10.7554/eLife.25541. PMID:28594323[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell. 2001 Mar;7(3):673-82. PMID:11463391
- ↑ Follis AV, Chipuk JE, Fisher JC, Yun MK, Grace CR, Nourse A, Baran K, Ou L, Min L, White SW, Green DR, Kriwacki RW. PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. Nat Chem Biol. 2013 Jan 20. doi: 10.1038/nchembio.1166. PMID:23340338 doi:http://dx.doi.org/10.1038/nchembio.1166
- ↑ Jenson JM, Ryan JA, Grant RA, Letai A, Keating AE. Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1. Elife. 2017 Jun 8;6. pii: e25541. doi: 10.7554/eLife.25541. PMID:28594323 doi:http://dx.doi.org/10.7554/eLife.25541
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