4UWH: PDB entry 4UWH

Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- butyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6- one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors. Determined by X-ray diffraction at 1.93 Å resolution. Released 26 Nov 2014.

Method: X-ray diffraction
Resolution: 1.93 Å
Organism: HOMO SAPIENS
Chains: 1
Atoms: 4,905
Mol. weight: 69.07 kDa
Ligands: JXM
Released: 26 Nov 2014

Explore 4UWH in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

4UWH contains 35 α-helices and 12 β-strands across 1 chain. 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: 35 helices, 12 β-strands

Element	Residues	Length	Sheet
α-helix	290-300	11
α-helix	306-309	4
α-helix	310-318	9
α-helix	320-323	4
α-helix	327-329	3
α-helix	330-334	5
α-helix	342-352	11
α-helix	360-365	6
α-helix	374-384	11
α-helix	389-402	14
α-helix	403-405	3
α-helix	408-413	6
α-helix	437-439	3
α-helix	442-444	3
α-helix	475-485	11
α-helix	487-502	16
α-helix	504-509	6
α-helix	511-529	19
α-helix	533-561	29
α-helix	566-578	13
α-helix	580-583	4
β-strand	591-593	3	1
β-strand	596-604	9	1
α-helix	606-608	3
β-strand	610-611	2	1
β-strand	619-625	7	1
β-strand	630-637	8	1
α-helix	642-660	19
β-strand	672-674	3	1
β-strand	679-683	5	1
α-helix	684-685	2
β-strand	688-689	2	2
α-helix	690-697	8
α-helix	700-707	8
β-strand	709	1	3
α-helix	714-716	3
β-strand	717	1	3
α-helix	719-738	20
β-strand	749-751	3	2
β-strand	757-759	3	2
α-helix	781-787	7
α-helix	793-811	19
α-helix	813-821	9
α-helix	829-832	4
α-helix	835-837	3
α-helix	838-846	9
α-helix	852-872	21

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Phosphatidylinositol 3-kinase catalytic subunit type 3	A	protein	601	HOMO SAPIENS	Q8NEB9 (AlphaFold model)

Sequence of entity 1 (A), FASTA

>4UWH_1 PHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT TYPE 3 (chains A)
GAMSDHDLKPNAATRDQLNIIVSYPPTKQLTYEEQDLVWKFRYYLTNQEKALTKFLKCVN
WDLPQEAKQALELLGKWKPMDVEDSLELLSSHYTNPTVRRYAVARLRQADDEDLLMYLLQ
LVQALKYENFDDIKNGLEPTKKDSQSSVSENVSNSGINSAEIDSSQIITSPLPSVSSPPP
ASKTKEVPDGENLEQDLCTFLISRACKNSTLANYLYWYVIVECEDQDTQQRDPKTHEMYL
NVMRRFSQALLKGDKSVRVMRSLLAAQQTFVDRLVHLMKAVQRESGNRKKKNERLQALLG
DNEKMNLSDVELIPLPLEPQVKIRGIIPETATLFKSALMPAQLFFKTEDGGKYPVIFKHG
DDLRQDQLILQIISLMDKLLRKENLDLKLTPYKVLATSTKHGFMQFIQSVPVAEVLDTEG
SIQNFFRKYAPSENGPNGISAEVMDTYVKSCAGYCVITYILGVGDRHLDNLLLTKTGKLF
HIDFGYILGRDPKPLPPPMKLNKEMVEGMGGTQSEQYQEFRKQCYTAFLHLRRYSNLILN
LFSLMVDANIPDIALEPDKTVKKVQDKFRLDLSDEEAVHYMQSLIDESVHALFAAVVEQI
H

Ligands and cofactors

ID	Name	Formula	Copies
JXM	(8S)-9-[(2R)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,…	C20 H23 F3 N4 O3	1

Water and common crystallization additives (NA) are not listed.

Primary citation

Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-Yl]-1-(3-Methyl-2-Oxo-Butyl)-2-(Trifluoromethyl)-3,4-Dihydro-2H-Pyrimido[1,2-A]Pyrimidin-6-One: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors. Pasquier, B., El-Ahmad, Y., Filoche-Romme, B. et al. J Med Chem (2015) 58:376. DOI 10.1021/JM5013352 · PubMed

Other PDB entries of the same protein (UniProt Q8NEB9 (AlphaFold model), which also has an AlphaFold model), best resolution first:

6HOG 1.26 Å, Structure of VPS34 LIR motif bound to GABARAP
7RSP 1.67 Å, Structure of the VPS34 kinase domain with compound 14
7RSV 1.78 Å, Structure of the VPS34 kinase domain with compound 5
7RSJ 1.88 Å, Structure of the VPS34 kinase domain with compound 14
9NIN 2.01 Å, The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-I-86
8RXR 2.06 Å, Crystal structure of VPS34 in complex with inhibitor SB02024
9ORM 2.06 Å, The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-I-137
6I3U 2.09 Å, Optimization of potent and selective ATM inhibitors suitable for a proof-of-concept…
9ZF4 2.09 Å, The structure of human Vacuolar Protein Sorting 34 catalytic domain bound to RD-II-83
9DKP 2.16 Å, The structure of human vacuolar protein sorting 34 catalytic domain bound to RD-I-53
3LS8 2.25 Å, Crystal structure of human PIK3C3 in complex with 3-[4-(4-Morpholinyl)thieno[3,2-d]pyrimi…
6HOH 2.25 Å, Structure of VPS34 LIR motif (S249E) bound to GABARAP

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