6uuo
From Proteopedia
(Difference between revisions)
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| - | == | + | ==Crystal structure of BRAF kinase domain bound to the PROTAC P4B== |
| - | <StructureSection load='6uuo' size='340' side='right'caption='[[6uuo]]' scene=''> | + | <StructureSection load='6uuo' size='340' side='right'caption='[[6uuo]], [[Resolution|resolution]] 3.29Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UUO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UUO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6uuo]] is a 2 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=6UUO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UUO FirstGlance]. <br> |
| - | </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=6uuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uuo OCA], [http://pdbe.org/6uuo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uuo RCSB], [http://www.ebi.ac.uk/pdbsum/6uuo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uuo ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QH1:1-[4-{[1-(3-{[dihydroxy(propyl)-lambda~4~-sulfanyl]amino}-2,6-difluorophenyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl](methyl)amino}pyridin-1(4H)-yl]ethan-1-one'>QH1</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRAF, BRAF1, RAFB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6uuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uuo OCA], [http://pdbe.org/6uuo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uuo RCSB], [http://www.ebi.ac.uk/pdbsum/6uuo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uuo ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN]] Note=Defects in BRAF are found in a wide range of cancers.<ref>PMID:18974108</ref> Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]].<ref>PMID:18974108</ref> Defects in BRAF are involved in lung cancer (LNCR) [MIM:[http://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.<ref>PMID:18974108</ref> <ref>PMID:12460919</ref> Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:[http://omim.org/entry/605027 605027]]. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.<ref>PMID:18974108</ref> <ref>PMID:14612909</ref> Defects in BRAF are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[http://omim.org/entry/115150 115150]]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.<ref>PMID:18974108</ref> Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM:[http://omim.org/entry/613706 613706]]. Noonan syndrome is a disorder characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.<ref>PMID:18974108</ref> <ref>PMID:19206169</ref> Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:[http://omim.org/entry/613707 613707]]. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.<ref>PMID:18974108</ref> <ref>PMID:19206169</ref> Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.<ref>PMID:18974108</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN]] Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF. | ||
| + | |||
| + | Functional characterization of a PROTAC directed against BRAF mutant V600E.,Posternak G, Tang X, Maisonneuve P, Jin T, Lavoie H, Daou S, Orlicky S, Goullet de Rugy T, Caldwell L, Chan K, Aman A, Prakesch M, Poda G, Mader P, Wong C, Maier S, Kitaygorodsky J, Larsen B, Colwill K, Yin Z, Ceccarelli DF, Batey RA, Taipale M, Kurinov I, Uehling D, Wrana J, Durocher D, Gingras AC, Al-Awar R, Therrien M, Sicheri F Nat Chem Biol. 2020 Aug 10. pii: 10.1038/s41589-020-0609-7. doi:, 10.1038/s41589-020-0609-7. PMID:32778845<ref>PMID:32778845</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6uuo" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Non-specific serine/threonine protein kinase]] |
| + | [[Category: Kurinov, I]] | ||
| + | [[Category: Maisonneuve, P]] | ||
| + | [[Category: Posternak, G]] | ||
| + | [[Category: Sicheri, F]] | ||
| + | [[Category: Complex]] | ||
| + | [[Category: Protac]] | ||
| + | [[Category: Signaling]] | ||
| + | [[Category: Signaling protein]] | ||
Revision as of 11:33, 26 August 2020
Crystal structure of BRAF kinase domain bound to the PROTAC P4B
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