5zya

From Proteopedia

(Difference between revisions)

Revision as of 22:56, 10 April 2020

SF3b spliceosomal complex bound to E7107

5zya, resolution 3.95Å

Structural highlights

5zya is a 4 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 5zd5. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	SF3B5 (HUMAN), SF3B1 (HUMAN), PHF5A (HUMAN), SF3B3 (HUMAN)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[SF3B3_HUMAN] Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron. [PHF5A_HUMAN] Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha. Also involved in pre-mRNA splicing.^[1] [SF3B1_HUMAN] Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron.

Publication Abstract from PubMed

Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 A. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1(R1074H) and PHF5A(Y36C) The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure-activity relationship (SAR) on the PHF5A(R38C) mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.

The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action.,Finci LI, Zhang X, Huang X, Zhou Q, Tsai J, Teng T, Agrawal A, Chan B, Irwin S, Karr C, Cook A, Zhu P, Reynolds D, Smith PG, Fekkes P, Buonamici S, Larsen NA Genes Dev. 2018 Feb 1;32(3-4):309-320. doi: 10.1101/gad.311043.117. PMID:29491137^[2]

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

References

↑ Will CL, Urlaub H, Achsel T, Gentzel M, Wilm M, Luhrmann R. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 2002 Sep 16;21(18):4978-88. PMID:12234937
↑ Finci LI, Zhang X, Huang X, Zhou Q, Tsai J, Teng T, Agrawal A, Chan B, Irwin S, Karr C, Cook A, Zhu P, Reynolds D, Smith PG, Fekkes P, Buonamici S, Larsen NA. The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. Genes Dev. 2018 Feb 1;32(3-4):309-320. doi: 10.1101/gad.311043.117. PMID:29491137 doi:http://dx.doi.org/10.1101/gad.311043.117

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/5zya"

@@ Line 3: / Line 3: @@
 <SX load='5zya' size='340' side='right' viewer='molstar' caption='[[5zya]], [[Resolution|resolution]] 3.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5zya]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5zd5 5zd5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZYA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZYA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5zya]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5zd5 5zd5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZYA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ZYA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9B0:[(2~{S},3~{S},4~{E},6~{S},7~{R},10~{R})-3,7-dimethyl-2-[(2~{E},4~{E},6~{R})-6-methyl-6-oxidanyl-7-[(2~{R},3~{R})-3-[(2~{R},3~{S})-3-oxidanylpentan-2-yl]oxiran-2-yl]hepta-2,4-dien-2-yl]-7,10-bis(oxidanyl)-12-oxidanylidene-1-oxacyclododec-4-en-6-yl]+4-cycloheptylpiperazine-1-carboxylate'>9B0</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9B0:[(2~{S},3~{S},4~{E},6~{S},7~{R},10~{R})-3,7-dimethyl-2-[(2~{E},4~{E},6~{R})-6-methyl-6-oxidanyl-7-[(2~{R},3~{R})-3-[(2~{R},3~{S})-3-oxidanylpentan-2-yl]oxiran-2-yl]hepta-2,4-dien-2-yl]-7,10-bis(oxidanyl)-12-oxidanylidene-1-oxacyclododec-4-en-6-yl]+4-cycloheptylpiperazine-1-carboxylate'>9B0</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SF3B5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SF3B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PHF5A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SF3B3 ([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=5zya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zya OCA], [http://pdbe.org/5zya PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zya RCSB], [http://www.ebi.ac.uk/pdbsum/5zya PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zya ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5zya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zya OCA], [http://pdbe.org/5zya PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zya RCSB], [http://www.ebi.ac.uk/pdbsum/5zya PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zya ProSAT]</span></td></tr>
 </table>
 == Function ==

5zya

From Proteopedia

Revision as of 22:56, 10 April 2020

SF3b spliceosomal complex bound to E7107

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox