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4mnf

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Revision as of 08:40, 10 April 2019

Crystal structure of BRAF-V600E bound to GDC0879

Structural highlights

4mnf 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:	,
Related:	4mne
Gene:	BRAF, BRAF1, RAFB1 (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[BRAF_HUMAN] Note=Defects in BRAF are found in a wide range of cancers.^[1] Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:114500].^[2] Defects in BRAF are involved in lung cancer (LNCR) [MIM: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.^[3] ^[4] Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM: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.^[5] ^[6] Defects in BRAF are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM: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.^[7] Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM: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.^[8] ^[9] Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:613707]. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.^[10] ^[11] 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.^[12]

Function

[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.

Publication Abstract from PubMed

Numerous oncogenic mutations occur within the BRAF kinase domain (BRAFKD). Here we show that stable BRAF-MEK1 complexes are enriched in BRAFWT and KRAS mutant (MT) cells but not in BRAFMT cells. The crystal structure of the BRAFKD in a complex with MEK1 reveals a face-to-face dimer sensitive to MEK1 phosphorylation but insensitive to BRAF dimerization. Structure-guided studies reveal that oncogenic BRAF mutations function by bypassing the requirement for BRAF dimerization for activity or weakening the interaction with MEK1. Finally, we show that conformation-specific BRAF inhibitors can sequester a dormant BRAF-MEK1 complex resulting in pathway inhibition. Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK.

Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling.,Haling JR, Sudhamsu J, Yen I, Sideris S, Sandoval W, Phung W, Bravo BJ, Giannetti AM, Peck A, Masselot A, Morales T, Smith D, Brandhuber BJ, Hymowitz SG, Malek S Cancer Cell. 2014 Aug 20. pii: S1535-6108(14)00299-2. doi:, 10.1016/j.ccr.2014.07.007. PMID:25155755^[13]

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

References

↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 2002 Dec 1;62(23):7001-3. PMID:12460919
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Lee JW, Yoo NJ, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Ko YH, Kim SH, Nam SW, Lee JY, Lee SH. BRAF mutations in non-Hodgkin's lymphoma. Br J Cancer. 2003 Nov 17;89(10):1958-60. PMID:14612909 doi:10.1038/sj.bjc.6601371
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955. PMID:19206169 doi:10.1002/humu.20955
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955. PMID:19206169 doi:10.1002/humu.20955
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Haling JR, Sudhamsu J, Yen I, Sideris S, Sandoval W, Phung W, Bravo BJ, Giannetti AM, Peck A, Masselot A, Morales T, Smith D, Brandhuber BJ, Hymowitz SG, Malek S. Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling. Cancer Cell. 2014 Aug 20. pii: S1535-6108(14)00299-2. doi:, 10.1016/j.ccr.2014.07.007. PMID:25155755 doi:http://dx.doi.org/10.1016/j.ccr.2014.07.007

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/4mnf"

@@ Line 1: / Line 1: @@
 ==Crystal structure of BRAF-V600E bound to GDC0879==
-<StructureSection load='4mnf' size='340' side='right' caption='[[4mnf]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='4mnf' size='340' side='right'caption='[[4mnf]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4mnf]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MNF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MNF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4mnf]] 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=4MNF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MNF FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=29L:2-{4-[(1E)-1-(HYDROXYIMINO)-2,3-DIHYDRO-1H-INDEN-5-YL]-3-(PYRIDIN-4-YL)-1H-PYRAZOL-1-YL}ETHANOL'>29L</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mne|4mne]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mnf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mnf OCA], [http://pdbe.org/4mnf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mnf RCSB], [http://www.ebi.ac.uk/pdbsum/4mnf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mnf ProSAT]</span></td></tr>
@@ Line 29: / Line 30: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Brandhuber, B]]
@@ Line 41: / Line 44: @@
 [[Category: Mapk]]
 [[Category: Pak]]
-[[Category: Raf]]
 [[Category: Ra]]
+[[Category: Raf]]
 [[Category: Transferase-transferase inhibitor complex]]

4mnf

From Proteopedia

Revision as of 08:40, 10 April 2019

Crystal structure of BRAF-V600E bound to GDC0879

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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