9AXH: KSR1/MEK1 complex heterotetramer with NST-628

Crystal structure of KSR1/MEK1 complex heterotetramer with NST-628. Determined by X-ray diffraction at 2.81 Å resolution. Released 17 Apr 2024.

Method: X-ray diffraction
Resolution: 2.81 Å
Organism: Homo sapiens
Chains: 4
Atoms: 8,453
Mol. weight: 137.3 kDa
Ligands: A1AHE, MG, ANP
Released: 17 Apr 2024

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

Secondary structure: helices and β-sheets

9AXH contains 62 α-helices and 38 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: 16 helices, 10 β-strands

Element	Residues	Length	Sheet
α-helix	41-43	3
α-helix	44-57	14
β-strand	68-77	10	1
β-strand	80-87	8	1
β-strand	93-100	8	1
α-helix	105-115	11
α-helix	116-120	5
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	163-184	22
α-helix	193-195	3
β-strand	196-198	3	2
β-strand	204-206	3	2
α-helix	213-219	7
β-strand	223	1	3
α-helix	232-235	4
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	371-379	9

Chain B: 17 helices, 10 β-strands

Element	Residues	Length	Sheet
α-helix	41-43	3
α-helix	44-57	14
α-helix	65-67	3
β-strand	68-77	10	4
β-strand	80-87	8	4
β-strand	93-100	8	4
α-helix	105-115	11
α-helix	116-120	5
β-strand	126	1	5
β-strand	129-135	7	4
β-strand	138-144	7	4
β-strand	150	1	5
α-helix	151-158	8
α-helix	163-184	22
α-helix	193-195	3
β-strand	196-198	3	5
β-strand	204-206	3	5
α-helix	213-219	7
β-strand	223-224	2	6
α-helix	232-235	4
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	371-379	9

Chain C: 14 helices, 9 β-strands

Element	Residues	Length	Sheet
β-strand	615-621	7	7
β-strand	626-642	17	7
α-helix	649-662	14
β-strand	669	1	8
β-strand	672-678	7	7
β-strand	681-687	7	7
β-strand	692-693	2	8
α-helix	694-698	5
α-helix	707-726	20
α-helix	736-738	3
β-strand	739-742	4	8
β-strand	745-748	4	8
β-strand	769-770	2	6
α-helix	773-778	6
α-helix	781-785	5
α-helix	793-795	3
α-helix	800-816	17
α-helix	826-834	9
α-helix	837-845	9
α-helix	850-859	10
α-helix	864-866	3
α-helix	868-869	2
α-helix	870-878	9

Chain D: 15 helices, 9 β-strands

Element	Residues	Length	Sheet
β-strand	618-621	4	7
β-strand	626-642	17	7
α-helix	652-662	11
β-strand	669	1	9
β-strand	672-678	7	7
β-strand	681-687	7	7
α-helix	688-690	3
β-strand	692-693	2	9
α-helix	694-698	5
α-helix	707-726	20
α-helix	736-738	3
β-strand	739-742	4	9
β-strand	745-748	4	9
β-strand	770	1	3
α-helix	773-776	4
α-helix	781-785	5
α-helix	793-795	3
α-helix	800-816	17
α-helix	826-834	9
α-helix	837-845	9
α-helix	850-859	10
α-helix	864-866	3
α-helix	868-869	2
α-helix	870-878	9

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Dual specificity mitogen-activated protein kinase kinase 1	A, B	protein	310	Homo sapiens	Q02750 (AlphaFold model)
Kinase suppressor of Ras 1	C, D	protein	283	Homo sapiens	Q8IVT5 (AlphaFold model)

Sequence of entity 1 (A, B), FASTA

>9AXH_1 Dual specificity mitogen-activated protein kinase kinase 1 (chains A, B)
GLEELELDEQQRKRLEAFLTQKQKVGELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMA
RKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVL
KKAGRIPEQILGKVSIAVIKGLTYLREKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQL
IDSMANSFVGTRSYMSPERLQGTHYSVQSDIWSMGLSLVEMAVGRYPIGSGSGSMAIFEL
LDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAFIKRSDAEEVDFAG
WLCSTIGLNQ

Sequence of entity 2 (C, D), FASTA

>9AXH_2 Kinase suppressor of Ras 1 (chains C, D)
GVYLQEWDIPFEQVELGEPIGQGRWGRVHRGRWHGEVAIRLLEMDGHNQDHLKLFKKEVM
NYRQTRHENVVLFMGACMNPPHLAIITSFCKGRTLHSFVRDPKTSLDINKTRQIAQEIIK
GMGYLHAKGIVHKDLKSKNVFYDNGKVVITDFGLFGISGVVREGRRENQLKLSHDWLCYL
APEIVREMTPGKDEDQLPFSKAADVYAFGTVWYELQARDWPLKNQAAEASIWQIGSGEGM
KRVLTSVSLGKEVSEILSACWAFDLQERPSFSLLMDMLEKLPK

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
MG	Magnesium ion	Mg	4
ANP	Phosphoaminophosphonic acid-adenylate ester	C10 H17 N6 O12 P3	4

Water and common crystallization additives (EDO, CL) 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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