PDB-9nc2: Structure of HPK1 with compound C3

ID or keywords:

Entry

Database: PDB / ID: 9nc2

Title

Structure of HPK1 with compound C3

Components

Mitogen-activated protein kinase kinase kinase kinase 1

Keywords

SIGNALING PROTEIN / kinase / cancer / inhibitor / HDX / molecular dynamics

Function / homology

Function and homology information

MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.5 Å

Authors

Kiefer, J.R. / Walters, B.T. / Wang, W. / Wu, P. / Duo, Y.

Funding support

1items

Citation

Journal: J.Chem.Inf.Model. / Year: 2025
Title: Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.
Authors: Walters, B.T. / Patapoff, A.W. / Kiefer, J.R. / Wu, P. / Wang, W.

History

Deposition	Feb 14, 2025	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Jun 25, 2025	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	9nc2.cif.gz	344.2 KB	Display	PDBx/mmCIF format
PDB format	pdb9nc2.ent.gz	282.9 KB	Display	PDB format
PDBx/mmJSON format	9nc2.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/nc/9nc2 ftp://data.pdbj.org/pub/pdb/validation_reports/nc/9nc2	HTTPS FTP

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Related structure data

Related structure data	9n48C 9n4uC 9n7rC 9n9xC 9nacC 9nbsC 9nbxC C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#234 - Jun 2019 MDM2 and Cancer similarity (1)

Deposited unit

A: Mitogen-activated protein kinase kinase kinase kinase 1

B: Mitogen-activated protein kinase kinase kinase kinase 1

hetero molecules

71.2 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Mitogen-activated protein kinase kinase kinase kinase 1

hetero molecules

defined by author
Evidence: gel filtration
35.5 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Mitogen-activated protein kinase kinase kinase kinase 1

hetero molecules

defined by author
35.7 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	52.006, 57.963, 61.562
Angle α, β, γ (deg.)	70.36, 66.43, 68.57
Int Tables number	1
Space group name H-M	P1

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Protein , 1 types, 2 molecules AB

#1: Protein	Mitogen-activated protein kinase kinase kinase kinase 1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEK kinase kinase 1 / MEKKK 1 Mass: 35018.434 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: Q92918, non-specific serine/threonine protein kinase

#1: Protein

Mitogen-activated protein kinase kinase kinase kinase 1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEK kinase kinase 1 / MEKKK 1

Mass: 35018.434 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host:

Spodoptera frugiperda (fall armyworm)
References: UniProt: Q92918, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 742 molecules

#2: Chemical	ChemComp-F97 / N-{2-(3,3-difluoropyrrolidin-1-yl)-6-[(3R)-pyrrolidin-3-yl]pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine Mass: 428.482 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₁H₂₆F₂N₈ / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂H₆O₂
#4: Chemical	ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₆H₁₃NO₄S / Comment: pH buffer*YM
#5: Chemical	ChemComp-NA / SODIUM ION Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 736 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y
Has protein modification	N

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.2 Å³/Da / Density % sol: 44.19 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, hanging drop / Details: as described

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Data collection

Diffraction	Mean temperature: 91 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
Detector	Type: RAYONIX MX-225 / Detector: CCD / Date: Mar 12, 2014
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.97872 Å / Relative weight: 1
Reflection	Resolution: 1.5→42.47 Å / Num. obs: 91469 / % possible obs: 93.9 % / Redundancy: 2.2 % / CC_1/2: 0.999 / R_merge(I) obs: 0.036 / R_pim(I) all: 0.032 / R_rim(I) all: 0.048 / Χ²: 0.71 / Net I/σ(I): 11.7
Reflection shell	Resolution: 1.5→1.59 Å / % possible obs: 94.1 % / Redundancy: 2.2 % / R_merge(I) obs: 0.246 / Num. measured all: 28924 / Num. unique obs: 13049 / CC_1/2: 0.883 / R_pim(I) all: 0.221 / R_rim(I) all: 0.331 / Χ²: 0.69 / Net I/σ(I) obs: 3.2

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Processing

Software

Name	Version	Classification
PHENIX	1.21.2_5419	refinement
Aimless		data scaling
XDS		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.5→27.5 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 2 / Phase error: 16.77 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.1822	4474	4.98 %
R_work	0.1581	-	-
obs	0.1593	89882	93.85 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL

Refinement step

Cycle: LAST / Resolution: 1.5→27.5 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	4482	0	80	736	5298

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.006	4724
X-RAY DIFFRACTION	f_angle_d	0.83	6410
X-RAY DIFFRACTION	f_dihedral_angle_d	15.606	1768
X-RAY DIFFRACTION	f_chiral_restr	0.049	713
X-RAY DIFFRACTION	f_plane_restr	0.009	801

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.5-1.52	0.2423	141	0.2253	2834	X-RAY DIFFRACTION	93
1.52-1.53	0.2322	136	0.1986	2893	X-RAY DIFFRACTION	94
1.53-1.55	0.2084	145	0.1892	2833	X-RAY DIFFRACTION	94
1.55-1.57	0.2068	175	0.1837	2887	X-RAY DIFFRACTION	94
1.57-1.59	0.2314	158	0.1857	2809	X-RAY DIFFRACTION	94
1.59-1.62	0.2329	132	0.1921	2882	X-RAY DIFFRACTION	95
1.62-1.64	0.235	157	0.1863	2857	X-RAY DIFFRACTION	94
1.64-1.66	0.227	156	0.1775	2869	X-RAY DIFFRACTION	95
1.66-1.69	0.1899	154	0.1691	2877	X-RAY DIFFRACTION	95
1.69-1.72	0.1887	150	0.1667	2890	X-RAY DIFFRACTION	95
1.72-1.75	0.2028	149	0.1616	2880	X-RAY DIFFRACTION	95
1.75-1.78	0.1908	154	0.1635	2855	X-RAY DIFFRACTION	95
1.78-1.81	0.1946	154	0.1642	2919	X-RAY DIFFRACTION	95
1.81-1.85	0.1853	137	0.1641	2880	X-RAY DIFFRACTION	95
1.85-1.89	0.1731	174	0.1709	2854	X-RAY DIFFRACTION	95
1.89-1.93	0.1903	163	0.1613	2920	X-RAY DIFFRACTION	95
1.93-1.98	0.1992	151	0.1607	2836	X-RAY DIFFRACTION	95
1.98-2.04	0.1781	154	0.1573	2861	X-RAY DIFFRACTION	95
2.04-2.1	0.152	163	0.1513	2871	X-RAY DIFFRACTION	94
2.1-2.16	0.1761	139	0.1479	2936	X-RAY DIFFRACTION	95
2.16-2.23	0.1668	147	0.1495	2484	X-RAY DIFFRACTION	92
2.26-2.33	0.1999	113	0.1432	2338	X-RAY DIFFRACTION	94
2.33-2.44	0.162	122	0.1489	2877	X-RAY DIFFRACTION	95
2.44-2.56	0.176	159	0.1419	2908	X-RAY DIFFRACTION	95
2.56-2.72	0.1905	122	0.1485	2925	X-RAY DIFFRACTION	95
2.73-2.94	0.1816	153	0.1594	2845	X-RAY DIFFRACTION	95
2.94-3.23	0.1666	153	0.1543	2900	X-RAY DIFFRACTION	95
3.23-3.7	0.1577	141	0.1471	2933	X-RAY DIFFRACTION	96
3.7-4.65	0.1659	160	0.1361	2924	X-RAY DIFFRACTION	97
4.65-27.5	0.1899	162	0.176	2831	X-RAY DIFFRACTION	94

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	0.0026	0.0018	-0.0013	0.0004	-0.0003	0.0008	0.0051	-0.006	0.0065	-0.0044	0.0041	-0.001	0.01	0.0037	-0	0.0258	-0.0239	0.0188	0.0862	0.0452	0.042	-31.9753	-68.6497	257.2941
2	0.0009	0.0006	-0.0014	0.0019	-0.0031	0.0019	-0.0135	0.0416	0.0147	0.0155	-0.0431	-0.0176	0.0193	0.0261	0	-0.0488	0.0503	-0.0517	-0.0241	0.048	-0.0327	-46.2971	-73.5231	257.2504
3	-0.001	0.0011	-0.0004	-0.0004	0.0011	0	-0.0001	-0.012	0.0062	-0.007	-0.0005	-0.0081	0.001	0.0121	0	0.0273	-0.027	0.0129	-0.0091	-0.0783	-0.0067	-49.3501	-90.5837	238.1054
4	0.0043	0.0011	0.0008	0.0044	-0.0034	0.0043	-0.0004	0.0066	-0.0095	0.0214	-0.0131	0.0132	0.0114	-0.0188	-0	0.0644	0.0033	-0.0022	0.0542	-0.0057	0.066	-61.8236	-83.0533	264.1555
5	-0.0013	-0.0035	0.0049	-0.0042	-0.002	0.0014	-0.0204	-0.0284	-0.0337	-0.0326	-0.0174	-0.0213	0.0094	0.0669	0	-0.0171	0.0208	-0.0221	0.0235	0.0603	-0.0702	-40.0636	-117.1097	229.8432
6	-0.0026	0.0008	-0.0008	-0.0006	0.0009	0.0006	-0.0265	-0.0153	0.0134	-0.0012	-0.0008	-0.0199	-0.0014	-0.0004	-0	0.0109	0.0143	0.0095	-0.0232	-0.0402	-0.0127	-49.7662	-103.6639	240.5917
7	0.0066	0.0042	-0.004	0.0043	-0.0003	0	-0.0209	0.0156	-0.0029	-0.0213	0.0181	-0.0063	-0.0277	-0.0224	0	0.0168	0.0194	0.0099	-0.0522	-0.0627	-0.0503	-60.3071	-104.4067	222.8086

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 3 through 49 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 50 through 156 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 157 through 193 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 194 through 292 )
5	X-RAY DIFFRACTION	5	chain 'B' and (resid 4 through 130 )
6	X-RAY DIFFRACTION	6	chain 'B' and (resid 131 through 193 )
7	X-RAY DIFFRACTION	7	chain 'B' and (resid 194 through 293 )

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