9AXX: PDB entry 9AXX

Crystal structure of BRAF/MEK1 complex with NST-628 and an active RAF dimer. Determined by X-ray diffraction at 2.07 Å resolution. Released 17 Apr 2024.

Method: X-ray diffraction
Resolution: 2.07 Å
Organism: Homo sapiens
Chains: 4
Atoms: 9,276
Mol. weight: 136.09 kDa
Ligands: ANP, MG, A1AHE
Released: 17 Apr 2024

Explore 9AXX in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

9AXX contains 67 α-helices and 46 β-strands across 4 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.

Chain A: 17 helices, 9 β-strands

Element	Residues	Length	Sheet
α-helix	44-58	15
α-helix	65-67	3
β-strand	68-77	10	1
β-strand	80-87	8	1
β-strand	93-100	8	1
α-helix	105-114	10
α-helix	115-120	6
β-strand	126	1	2
β-strand	129-134	6	1
β-strand	138-144	7	1
β-strand	150	1	2
α-helix	151-158	8
α-helix	163-184	22
α-helix	193-195	3
β-strand	196-198	3	2
β-strand	204-206	3	2
α-helix	213-218	6
α-helix	232-235	4
α-helix	243-258	16
α-helix	310-319	10
α-helix	321-323	3
α-helix	325-326	2
α-helix	332-342	11
α-helix	352-356	5
α-helix	359-365	7
α-helix	371-379	9

Chain B: 17 helices, 12 β-strands

Element	Residues	Length	Sheet
β-strand	451	1	3
α-helix	452-453	2
α-helix	454-456	3
α-helix	457	1
β-strand	458-462	5	3
β-strand	471-475	5	3
β-strand	479-485	7	3
α-helix	492-505	14
β-strand	513	1	4
β-strand	516-520	5	3
β-strand	525-530	6	3
α-helix	531-533	3
β-strand	536	1	4
α-helix	537-542	6
α-helix	550-569	20
β-strand	572-573	2	5
α-helix	579-581	3
β-strand	582-585	4	4
β-strand	589-592	4	4
β-strand	599-600	2	5
α-helix	617-619	3
α-helix	622-626	5
α-helix	635-651	17
α-helix	662-670	9
α-helix	678-680	3
α-helix	687-696	10
α-helix	701-703	3
α-helix	705-706	2
α-helix	707-719	13

Chain C: 17 helices, 10 β-strands

Element	Residues	Length	Sheet
α-helix	44-58	15
α-helix	65-67	3
β-strand	68-76	9	6
β-strand	81-87	7	6
β-strand	93-100	8	6
α-helix	105-115	11
α-helix	116-120	5
β-strand	123	1	7
β-strand	126	1	7
β-strand	129-135	7	6
β-strand	138-144	7	6
β-strand	149-150	2	7
α-helix	151-156	6
α-helix	163-179	17
α-helix	180-184	5
α-helix	193-195	3
β-strand	196-198	3	7
β-strand	204-206	3	7
α-helix	213-218	6
α-helix	232-235	4
α-helix	243-258	16
α-helix	310-319	10
α-helix	321-323	3
α-helix	332-341	10
α-helix	352-356	5
α-helix	359-366	8
α-helix	371-377	7

Chain D: 16 helices, 15 β-strands

Element	Residues	Length	Sheet
β-strand	451	1	8
α-helix	452-453	2
α-helix	457	1
β-strand	458-465	8	8
β-strand	470-475	6	8
β-strand	479-484	6	8
α-helix	492-505	14
β-strand	513	1	9
β-strand	516-520	5	8
β-strand	526-530	5	8
β-strand	536	1	9
α-helix	537-538	2
α-helix	539-543	5
α-helix	550-569	20
β-strand	572-573	2	10
α-helix	579-581	3
β-strand	582-585	4	9
β-strand	589-592	4	9
β-strand	599-600	2	10
β-strand	603	1	10
β-strand	604	1	11
β-strand	607	1	11
α-helix	617-619	3
α-helix	622-626	5
α-helix	635-651	17
α-helix	662-670	9
α-helix	678-680	3
α-helix	687-696	10
α-helix	701-703	3
α-helix	705-706	2
α-helix	707-719	13

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Dual specificity mitogen-activated protein kinase kinase 1	A, C	protein	310	Homo sapiens	Q02750 (AlphaFold model)
Serine/threonine-protein kinase B-raf	B, D	protein	280	Homo sapiens	P15056 (AlphaFold model)

Sequence of entity 1 (A, C), FASTA

>9AXX_1 Dual specificity mitogen-activated protein kinase kinase 1 (chains A, C)
GLEELELDEQQRKRLEAFLTQKQKVGELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMA
RKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVL
KKAGRIPEQILGKVSIAVIKGLTYLREKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQL
IDAMANAFVGTRSYMSPERLQGTHYSVQSDIWSMGLSLVEMAVGRYPIGSGSGSMAIFEL
LDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAFIKRSDAEEVDFAG
WLCSTIGLNQ

Sequence of entity 2 (B, D), FASTA

>9AXX_2 Serine/threonine-protein kinase B-raf (chains B, D)
GDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVG
VLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQG
MDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATVKSRWSGSHQFEQLSGSILWMAPE
VIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRS
NCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPK

Ligands and cofactors

ID	Name	Formula	Copies
ANP	Phosphoaminophosphonic acid-adenylate ester	C10 H17 N6 O12 P3	3
MG	Magnesium ion	Mg	2
A1AHE	N-[3-fluoro-4-({7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxo-2H-1-benzopyran-3-…	C22 H18 F2 N4 O5 S	2

Water and common crystallization additives (TRS, EDO) are not listed.

Primary citation

The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers. Ryan, M.B., Quade, B., Schenk, N. et al. Cancer Discov (2024) 14:1190-1205. DOI 10.1158/2159-8290.CD-24-0139 · PubMed

Other PDB entries of the same protein (UniProt Q02750 (AlphaFold model), which also has an AlphaFold model), best resolution first:

7B7R 1.7 Å, MEK1 in complex with compound 4
7B9L 1.7 Å, MEK1 in complex with compound 23
3EQC 1.8 Å, X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a…
3EQI 1.9 Å, X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a…
3EQH 2.0 Å, X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a…
3VVH 2.0 Å, X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in complex…
7B94 2.0 Å, MEK1 in complex with compound 6
7F2X 2.01 Å, Crystal structure of MEK1 C121S mutant
3EQD 2.1 Å, X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a…
4AN3 2.1 Å, Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518…
7XLP 2.1 Å, MEK1 bound to DS03090629
7XNC 2.1 Å, MEK1 bound to DS94070624

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