{"database":"Pride","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Msf":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne.msf","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne.msf","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe.msf"],"Raw":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F5.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F7.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F3.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F1.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F1.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F2.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F6.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F6.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F4.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F2.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F6.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F5.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F5.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F3.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F7.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F1.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F4.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F7.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne_TMT_F4.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe_TMT_F2.raw","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne_TMT_F3.raw"],"Other":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/IA_Alkyne.pdResult","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/ArSq_Alkyne.pdResult","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063040/NoProbe.pdResult"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"labhead_mail":["George.Burslem@pennmedicine.upenn.edu"],"submitter":["George M Burslem"],"technology_type":["Mass Spectrometry","Bottom-up proteomics"],"software":[""],"submitter_keywords":["Chemoproteomics","Vemurafenib","Mek1/2","Arsq-alkyne","Cysteine and lysine ligandability","Tmt","Braf","Click chemistry","Ia-alkyne","Mass spectrometry","Trametinib","Abpp"],"full_dataset_link":["https://www.ebi.ac.uk/pride/archive/projects/PXD063040"],"tissue":["Melanocyte"],"sample_protocol":["Sample Collection and Preparation  Treated cells were washed with cold 1X PBS (phosphate buffered saline) and then collected via scrapping in 1 mL of cold 1X PBS and transferred to 1.7 mL microcentrifuge tubes (Genesee Scientific, catalog#24-282). The cells were centrifuged at 2000 rpm for 3 minutes and then resuspended in 500 µL of cold 1X PBS. Each resuspended cell pellet was then sonicated (Fisher Scientific, catalog# FB120110) for 2 rounds of 10 pulses for 1 second at 25% power with 10 minutes in between sonication rounds. The sonicated resuspended cell pellets were first centrifuged for 12,000 rpm for 5 minutes at 4oC and then transferred to ultracentrifuge tubes (Labcon, catalog#3016-870-000) to be centrifuged at 45,000 rpm at 4oC for 30 minutes in Sorvall MX120 Plus micro-ultracentrifuge to separate soluble and insoluble protein fractions. The soluble protein samples were transferred back to 1.7 mL microcentrifuge tubes. The protein concentration was determined by Peirce BCA Protein Assay Kit (Thermo Scientific, catalog#23227) using BSA as a standard.  Click Chemistry Reaction  The general click reaction mix per 25 µL reaction volume was: 1.5 µL of 1.7 mM Tris-benzyltriazolylmethyl-amine (TBTA, Cayman Chemical Company, catalog #18816, in DMSO), 0.5 µL of 50mM CuSO4 (Sigma-Aldrich, catalog #C8027-500G, in Milli-Q H2O), 0.5 µL of 13 mg/mL Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, Sigma-Aldrich, catalog #C4706-2G, in H2O), and 0.5 uL of 100 mM Biotin Azide (Specifications below for specific applications). The master mix reagents are added in the order listed above to each respective sample and incubated at room temperature for one hour.   Tryptic Digest  Fresh 100 mM DTT (Thermo Scientific, catalog #R0861) was added so that the final concentration in the samples was 10 mM, and the samples were incubated at 60oC for 20 minutes. Then fresh 10mM Iodoacetamide (Thermo Scientific, catalog #122271000) was added to each sample to a final concentration of 20 mM, and the samples were incubated at room temperature in the dark for 10 minutes. Finally, Trypsin/Lys C mix, Mass Spec Grade (Promega, catalog #V5072) was added to each sample in a protein ratio of 1:100. The samples were then incubated with shaking at 37oC overnight.  The next day, formic acid was added (0.1% of sample volume) to quench the reaction.   Tandem mass tag (TMT) labeling  Tandem mass tag (TMT) labeling of peptides was performed according to the manufacturer’s instructions. Briefly, peptides underwent C18 cleanup and were reconstituted in 100 mM triethylammonium bicarbonate (TEABC) buffer (pH ~8.0). The TMT kit was equilibrated to room temperature, and each tag was reconstituted in 50 μL of anhydrous acetonitrile (ACN) with gentle vortexing. Three independent TMT experiments were set up: one with the cysteine reactive probe IA-alkyne, another with the lysine reactive probe ArSq-alkyne, and one without any probe. In each of these probe conditions, there were three replicates of A375 samples treated with vehicle (DMSO), 100 nM Trametinib, and 1 μM Vemurafenib.  TMT reagents were added and the labeling reactions were incubated at room temperature for 1 hour. To assess labeling efficiency, an equal volume (2 μL) from each sample was pooled and labelling efficiency determined by LC-MS/MS. Following the label check evaluation, the reaction was quenched by adding 5% hydroxylamine and incubated for 15 minutes. Samples were then pooled and vacuum dried.  To enhance proteome depth, C18 spin column-based fractionation was performed using a stepwise acetonitrile gradient (5–50%). Each sample was fractionated into 14 fractions, which were subsequently concatenated into 7 fractions. Samples were vacuum dried and stored at -20°C until LC-MS/MS analysis.  LC-MS/MS Analysis  LC-MS/MS analysis was performed on a Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer (Thermo Scientific, Bremen, Germany) coupled with a Vanquish Neo UHPLC system (Thermo Scientific). Labelled peptides were reconstituted in 0.1% formic acid and separated on an analytical column (75 μm × 15 cm; 3 μm C18 100Å; Thermo Scientific, PepMap™ RSLC, PN ES900) at a flow rate of 350 nL/min. A linear gradient of 4–35% solvent B (0.1% formic acid in 80% acetonitrile) was applied over 100 minutes, with a total run time of 120 minutes.  MS and MS/MS data were acquired using the Orbitrap analyzer at resolutions of 70,000 and 35,000, respectively. Precursor MS scans were performed in the m/z range of 350–1500, with a maximum ion injection time of 50 msec and an AGC target of 3e6 ions. The mass spectrometer operated in DDA mode, selecting top 10 precursor ions using a quadrupole mass filter with an isolation window of 1.2 m/z and a dynamic exclusion of 45 seconds. Fragmentation of isolated ions was performed using high-energy collision-induced dissociation (HCD) with an NCE of 30%. MS/MS scans were acquired with a maximum ion injection time of 250 msec and an AGC target of 2e5."],"repository":["Pride"],"quantification_method":[""],"modification":[""],"data_protocol":["Data Analysis  Data analysis was performed using the Proteome Discoverer platform (version 3.0.0.757; Thermo Scientific). Mass spectrometry raw (.raw) files were searched against the Human UniProt database using the SEQUEST search algorithm. TMT labeling at the peptide N-terminus/lysine residue and carbamidomethylation at cysteine residues were set as static modifications, while methionine oxidation was considered a variable modification. False discovery rate (FDR) of 5% was applied at both the PSM and peptide levels and a precursor mass tolerance of 20 ppm and a fragment mass tolerance of 0.05 Da were used. Trypsin was specified as the protease, allowing a maximum of two missed cleavages.   Streptavidin Pulldown  The Streptavidin Magnetic Beads (New England Biolabs, catalog #S1420S) were prepared by washing three times with a conjugation buffer (PBS + 500 mM NaCl), maintaining the beads in a 1:1 slurry. Per each reaction, the biotinylated sample was then mixed with 1 mL of conjugation buffer and 100 µL of the washed 1:1 Streptavidin bead slurry. The samples were then rotated for two hours at room temperature.  After rotating, the samples were washed nine times in total: three times with a wash buffer (PBS + 500 mM NaCl + 0.1% Tween 20), three times with PBS, and three times with MilliQ water."],"omics_type":["Proteomics"],"labhead":["George Burslem"],"instrument_platform":[""],"submission_type":["PARTIAL"],"labhead_affiliation":["University of Pennsylvania"],"species":["Homo Sapiens (human)"],"publication":["42006249 Jarvis AF, Bhat MY, Maujean T, Abreu AL, Toy K, Burslem GM, Brady DC. MAPK Pathway Inhibition Reshapes Kinase Chemical Probe Reactivity Reflecting Cellular Activation States. ACS Bio Med Chem Au. 2026 6(2):178-191 10.1021/acsbiomedchemau.5c00231"],"submitter_mail":["george.burslem@pennmedicine.upenn.edu"],"submitter_affiliation":["University of Pennsylvania"],"submitter_country":["United States"],"pubmed_abstract":["Despite the pivotal role of oncogenic kinases in cancer initiation, progression, and therapeutic resistance, functionally profiling their activity and conformational dynamics in live cells remains challenging. Existing methods often fail to capture inhibitor-bound structural states of kinases, particularly in clinically relevant contexts, such as treatment response and acquired resistance, where genomic data alone are insufficient. Here, we use activity-based protein profiling (ABPP) to monitor composite amino acid reactivity changes, across cysteine, lysine, and carboxylic acid residues, as a hypothesis-generating readout of kinase state in live cells. Using electrophilic probes, we show that treatment of BRAFV600E mutant melanoma cells with vemurafenib or trametinib decreases overall cysteine and lysine reactivity in BRAFV600E and MEK1/2, likely reflecting composite changes in amino acid accessibility across multiple reactive residues associated with inhibitor binding. Changing the order of probe addition and inhibitor treatment altered the labeling outcomes, consistent with competitive engagement and structural stabilization. Comparative analysis of ATP-competitive BRAFV600E inhibitors vemurafenib and dabrafenib indicated differences in aspartate and glutamate labeling patterns, consistent with the possibility that ABPP may detect inhibitor-associated variations in residue accessibility, which could reflect differences in inhibitor-bound conformations. In inhibitor-resistant melanoma models, ABPP detected differences in residue reactivity relative to parental cells, which aligned with known resistance-associated features, such as BRAF overexpression and the MEK2 Q60P activation mutation. Moreover, global proteome analyses of cysteine and lysine reactivity upon BRAFV600E inhibition revealed probe-accessible cysteine labeling changes on KSR2, suggesting a potential MAPK pathway remodeling. Together, these findings highlight ABPP as a valuable chemical biology approach for investigating inhibitor-dependent changes in kinase residue reactivity, offering a framework to investigate how kinase conformational dynamics and signaling pathway adaptation influence the therapeutic response and resistance in cancer."],"pubmed_title":["MAPK Pathway Inhibition Reshapes Kinase Chemical Probe Reactivity Reflecting Cellular Activation States."],"pubmed_authors":["Jarvis Andrew F AF, Bhat Mohd Younis MY, Maujean Timothé T, Abreu Ahlenne L AL, Toy Kaitlyn K, Burslem George M GM, Brady Donita C DC"],"additional_accession":[]},"is_claimable":false,"name":"MAPK Pathway Inhibition Reshapes Kinase Chemoproteomic Ligandability Reporting on Cellular Activation States","description":"Despite the pivotal role of oncogenic kinases in cancer initiation, progression, and resistance, functional profiling of their conformational states within cells remains challenging. Current methodologies often struggle to capture the dynamic structural features and inhibitor-bound conformations of these kinases, particularly in clinically relevant scenarios such as treatment response and relapse, where genomic characterization alone is insufficient.  Chemoproteomic techniques, including activity-based protein profiling (ABPP), offer a powerful means to assess amino acid reactivity in situ as a proxy for protein structure and function. Here, we report that treatment of BRAF mutation positive melanoma cell lines with the BRAF and MEK1/2 inhibitors, vemurafenib and trametinib respectively, results in a significant decrease in cysteine and lysine residue accessibility, consistent with inhibitor-induced conformational changes. Comparison of two ATP-competitive BRAF inhibitors, vemurafenib and dabrafenib, revealed distinct labelling patterns at the DFG-motif aspartate, demonstrating the ability of ABPP to resolve functional residue accessibility within kinase active sites. In melanoma cell lines with acquired resistance to BRAF or MEK inhibition, ABPP identified altered residue specific probe reactivity consistent with mutation-driven conformational shifts. Mass spectrometry validation further revealed similar accessibility changes in MAPK pathway components, including KSR2, suggesting broader pathway-level remodelling. These findings support the utility of ABPP for probing conformational dynamics, ligandability, and resistance-associated structural adaptations in kinases and related signalling proteins.","dates":{"publication":"2026-05-13","submission":"2025-04-16"},"accession":"PXD063040","cross_references":{"TAXONOMY":["NEWT:330879","NEWT:377960","NEWT:2042546","NEWT:259447","NEWT:295546","NCBITaxon:2719036","NCBITaxon:1280","NEWT:112503","NEWT:1129","NEWT:309807","NEWT:59753","NEWT:89184","NEWT:309800","NEWT:281395","NEWT:1211601","NEWT:876138","NEWT:44271","NEWT:193516","NEWT:1117","NEWT:498257","NEWT:10036","NEWT:1590","NEWT:661410","NEWT:638632","NEWT:224326","NEWT:376619","NCBITaxon:79857","NEWT:1096976","NEWT:1589","NEWT:135622","NEWT:35786","NEWT:1580","NEWT:399784","NEWT:96731","NEWT:383379","NEWT:418106","NEWT:10029","NEWT:913645","NEWT:641809","NEWT:317447","NEWT:4688","NEWT:7719","NEWT:868565","NEWT:135674","NEWT:79329","NEWT:30069","NEWT:12637","NEWT:59729","NEWT:2164133","NEWT:295105","NEWT:108061","NEWT:60711","NEWT:224308","NEWT:3347","NEWT:160621","NEWT:212790","NEWT:1310161","NEWT:77133","NEWT:145481","NEWT:1310165","NEWT:29058","NCBITaxon:79824","NEWT:44688","NEWT:44689","NEWT:498211","NEWT:347256","NEWT:5518","NEWT:398007","NEWT:1527468","NEWT:498217","NEWT:498216","NEWT:11320","NEWT:246196","NEWT:246197","NEWT:145458","NEWT:44685","NEWT:161934","NEWT:1148","NEWT:5508","NEWT:3329","NEWT:5507","NEWT:410661","NEWT:1140","NCBITaxon:2157","NEWT:1143","NEWT:1287689","NEWT:1094343","NEWT:1462472","NEWT:1336795","NEWT:644042","NEWT:1182590","NEWT:3712","NEWT:3711","NEWT:270643","NEWT:2065263","NEWT:177437","NEWT:10418","NEWT:118698","NEWT:1616117","NEWT:118696","NEWT:34865","NEWT:52283","NEWT:284812","NEWT:8175","NEWT:43330","NEWT:1603293","NEWT:44664","NEWT:3702","NEWT:1245466","NEWT:244366","NEWT:1246791","NEWT:118694","NEWT:2850","NEWT:118691","NEWT:34871","NEWT:33548","NEWT:96794","NEWT:3708","NEWT:332648","NEWT:44670","NEWT:536231","NEWT:376219","NEWT:219813","NEWT:1510","NEWT:460519","NEWT:1515","NEWT:572307","NEWT:1432138","NEWT:1424507","NEWT:1194599","NEWT:272844","NEWT:1303443","NEWT:9483","NEWT:485","NEWT:56636","NEWT:2853422","NEWT:1679718","NEWT:480","NEWT:67767","NEWT:46835","NEWT:109757","NEWT:582580","NEWT:1502","NEWT:128017","NEWT:376686","NEWT:95486","NEWT:1883446","NEWT:1233435","NEWT:109760","NEWT:29031","NEWT:235443","NEWT:108458","NEWT:5936","NEWT:320637","NEWT:3750","NEWT:983964","NEWT:11706","NEWT:32644","NEWT:527796","NEWT:499175","NEWT:109779","NEWT:3745","NEWT:1715989","NCBITaxon:4751","NEWT:3747","NEWT:1116234","NEWT:1255228","NEWT:410289","NEWT:373153","NEWT:472","NEWT:1071661","NEWT:470","NEWT:5911","NCBITaxon:50557","NEWT:39251","NEWT:29491","NEWT:101841","NEWT:446","NEWT:153481","NEWT:2014887","NEWT:33952","NEWT:445","NEWT:153009","NEWT:261756","NEWT:63366","NEWT:63367","NEWT:215402","NEWT:1547","NEWT:9031","NEWT:27292","NEWT:108931","NEWT:1293497","NEWT:1055524","NEWT:150475","NEWT:267872","NEWT:172269","NEWT:9534","NEWT:5180","NEWT:256737","NEWT:9541","NEWT:8694","NEWT:33936","NEWT:8692","NEWT:2903","NEWT:185579","NEWT:13076","NEWT:1006581","NEWT:33940","NEWT:550","NEWT:554","NEWT:451516","NEWT:552","NEWT:1325291","NEWT:36185","NEWT:1054211","NEWT:1225786","NEWT:575412","NEWT:28112","NEWT:6493","NEWT:6494","NEWT:6491","NEWT:507601","NEWT:520","NEWT:186441","NEWT:643680","NEWT:214092","NCBITaxon:6157","NEWT:13095","NEWT:162425","NEWT:104105","NEWT:216257","NEWT:9986","NEWT:8654","NEWT:8658","NEWT:1268063","NEWT:8657","NEWT:8655","NEWT:5147","NEWT:28104","NEWT:407821","NCBITaxon:2","NEWT:568708","NEWT:986","NEWT:52641","NEWT:28532","NEWT:353152","NEWT:40674","NEWT:1194669","NEWT:443906","NEWT:519","NEWT:2510939","NEWT:6063","NEWT:1328388","NEWT:1548728","NEWT:667127","NEWT:9557","NEWT:377586","NEWT:300641","NEWT:39655","NEWT:9554","NEWT:38323","NEWT:256318","NEWT:206411","NCBITaxon:6191","NEWT:229533","NEWT:214053","NEWT:80863","NEWT:90675","NEWT:52638","NEWT:57075","NEWT:8697","NEWT:8695","NEWT:884204","NEWT:1123869","NEWT:9544","NEWT:9545","NEWT:979","NEWT:7370","NEWT:83906","NEWT:1134506","NEWT:255470","NEWT:38783","NEWT:6426","NEWT:33090","NEWT:9935","NEWT:287889","NEWT:305959","NEWT:92867","NEWT:92866","NCBITaxon:3055","NEWT:51750","NEWT:202950","NEWT:295027","NCBITaxon:11320","NEWT:632957","NEWT:9925","NCBITaxon:9606","NEWT:90690","NEWT:1436183","NEWT:4232","NEWT:416348","NEWT:11298","NEWT:196627","NEWT:200308","NEWT:200302","NEWT:870435","NEWT:9913","NEWT:9915","NEWT:105841","NEWT:2666255","NEWT:999810","NCBITaxon:5693","NEWT:28995","NEWT:1392998","NEWT:380394","NEWT:226900","NEWT:1266738","NEWT:231490","NEWT:244704","NEWT:7725","NEWT:430615","NEWT:72664","NEWT:326423","NEWT:452467","NEWT:198822","NEWT:36111","NEWT:326424","NEWT:1678078","NEWT:749906","NEWT:418985","NEWT:749907","NEWT:150847","NEWT:431947","NEWT:69014","NEWT:142809","NEWT:302409","NEWT:130821","NEWT:27606","NEWT:1519788","NEWT:59202","NEWT:9975","NEWT:8643","NEWT:1159899","NEWT:502780","NEWT:860688","NEWT:13443","NEWT:8644","NEWT:5141","NEWT:46360","NCBITaxon:3044782","NEWT:202914","NEWT:160235","NEWT:502779","NEWT:297246","NEWT:8639","NEWT:1928434","NEWT:8637","NEWT:1114970","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