9AXM: ARAF/MEK1 complex with NST-628 and a RAF dimer

Crystal structure of ARAF/MEK1 complex with NST-628 and a RAF dimer. Determined by X-ray diffraction at 2.42 Å resolution. Released 17 Apr 2024.

Method: X-ray diffraction
Resolution: 2.42 Å
Organism: Homo sapiens
Chains: 4
Atoms: 8,435
Mol. weight: 134.91 kDa
Ligands: A1AHE, ANP, MG
Released: 17 Apr 2024

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

Secondary structure: helices and β-sheets

9AXM contains 64 α-helices and 43 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, 10 β-strands

Element	Residues	Length	Sheet
α-helix	44-58	15
α-helix	65-67	3
β-strand	68-76	9	1
β-strand	80-87	8	1
β-strand	92-100	9	1
α-helix	105-114	10
α-helix	115-120	6
β-strand	126	1	2
β-strand	129-135	7	1
β-strand	138-144	7	1
β-strand	149-150	2	2
α-helix	151-158	8
α-helix	163-183	21
α-helix	193-195	3
β-strand	196-198	3	2
β-strand	204-206	3	2
α-helix	213-218	6
β-strand	223	1	3
α-helix	238-240	3
α-helix	242-258	17
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	371-373	3
α-helix	374-379	6

Chain B: 15 helices, 11 β-strands

Element	Residues	Length	Sheet
β-strand	304	1	4
α-helix	307-309	3
β-strand	311-318	8	4
β-strand	322-328	7	4
β-strand	332-338	7	4
α-helix	349-358	10
β-strand	366	1	5
β-strand	369-373	5	4
β-strand	379-383	5	4
α-helix	384-386	3
β-strand	389	1	5
α-helix	390-395	6
α-helix	403-422	20
α-helix	432-434	3
β-strand	435-438	4	5
β-strand	442-445	4	5
β-strand	469	1	3
α-helix	470-472	3
α-helix	475-479	5
α-helix	488-504	17
α-helix	515-524	10
α-helix	531-533	3
α-helix	540-549	10
α-helix	554-556	3
α-helix	558-559	2
α-helix	560-572	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	80-87	8	6
β-strand	92-100	9	6
α-helix	105-114	10
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	151-158	8
α-helix	163-182	20
α-helix	193-195	3
β-strand	196-198	3	7
β-strand	204-206	3	7
α-helix	213-218	6
α-helix	232-236	5
α-helix	243-258	16
α-helix	310-318	9
α-helix	321-323	3
α-helix	332-341	10
α-helix	350-351	2
α-helix	352-356	5
α-helix	359-366	8
α-helix	371-375	5

Chain D: 15 helices, 12 β-strands

Element	Residues	Length	Sheet
α-helix	301-303	3
β-strand	304	1	8
α-helix	307-309	3
β-strand	311-317	7	8
β-strand	323-328	6	8
β-strand	332-337	6	8
α-helix	345-359	15
β-strand	366	1	9
β-strand	369-373	5	8
β-strand	379-383	5	8
α-helix	384-386	3
β-strand	387-389	3	9
α-helix	390-395	6
α-helix	403-422	20
β-strand	425-426	2	10
α-helix	432-434	3
β-strand	435-438	4	9
β-strand	442-445	4	9
β-strand	452-453	2	10
α-helix	475-479	5
α-helix	488-504	17
α-helix	515-524	10
α-helix	531-533	3
α-helix	540-549	10
α-helix	554-556	3
α-helix	558-559	2
α-helix	560-572	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 A-Raf	B, D	protein	280	Homo sapiens	P10398 (AlphaFold model)

Sequence of entity 1 (A, C), FASTA

>9AXM_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

>9AXM_2 Serine/threonine-protein kinase A-Raf (chains B, D)
GDSGDDWEVPPSEVQLLKRIGTGSFGTVFRGRWHGDVAVKVLKVSQPTAEQAQAFKNEMQ
VLRKTRHVNILLFMGFMTRPGFAIITQWCEGSSLYHHLHVADTRFDMVQLIDVARQTAQG
MDYLHAKNIIHRDLKSNNIFLHEGLTVKIGDFGLATVKTRWSGAQPLEQPSGSVLWMAAE
VIRMQDPNPYSFQSDVYAYGVVLYELMTGSLPYSHIGCRDQIIFMVGRGYLSPDLSKISS
NCPKAMRRLLSDCLKFQREERPLFPQILATIELLQRSLPK

Ligands and cofactors

ID	Name	Formula	Copies
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
ANP	Phosphoaminophosphonic acid-adenylate ester	C10 H17 N6 O12 P3	2
MG	Magnesium ion	Mg	2

Water and common crystallization additives (GOL, 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
9AXX 2.07 Å, Crystal structure of BRAF/MEK1 complex with NST-628 and an active RAF dimer
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

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