8SBC: PDB entry 8SBC

Co-structure of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform and brain penetrant inhibitors. Determined by X-ray diffraction at 2.3 Å resolution. Released 19 Jul 2023.

Method: X-ray diffraction
Resolution: 2.3 Å
Organism: Homo sapiens
Chains: 2
Atoms: 9,749
Mol. weight: 160.92 kDa
Ligands: ZTV
Released: 19 Jul 2023

Explore 8SBC in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

8SBC contains 62 α-helices and 54 β-strands across 2 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: 55 helices, 46 β-strands

Element	Residues	Length	Sheet
β-strand	10	1	1
β-strand	13	1	1
β-strand	19-25	7	2
β-strand	31-37	7	2
β-strand	41	1	3
α-helix	42-52	11
α-helix	53-55	3
α-helix	59-61	3
α-helix	65-67	3
β-strand	69-73	5	2
β-strand	74	1	4
β-strand	79-82	4	2
β-strand	88	1	3
α-helix	89-91	3
β-strand	94	1	4
β-strand	98-102	5	2
α-helix	108-121	14
α-helix	126-130	5
α-helix	134-142	9
α-helix	144-154	11
α-helix	159-166	8
β-strand	171	1	5
α-helix	176-178	3
α-helix	179-182	4
β-strand	189-194	6	6
β-strand	207-212	6	6
α-helix	217-222	6
β-strand	252-254	3	6
β-strand	260-261	2	6
α-helix	267-269	3
β-strand	270	1	5
α-helix	271-279	9
β-strand	284-287	4	6
α-helix	290-294	5
α-helix	306-309	4
β-strand	324-326	3	7
β-strand	333-341	9	8
β-strand	353-362	10	9
β-strand	365-366	2	9
β-strand	371-372	2	9
β-strand	376	1	9
β-strand	382-392	11	8
α-helix	393-395	3
β-strand	401-410	10	9
β-strand	418-428	11	9
β-strand	430	1	10
β-strand	435	1	7
β-strand	436	1	10
α-helix	437	1
β-strand	439-444	6	8
α-helix	445	1
β-strand	446-447	2	9
α-helix	448-449	2
α-helix	461	1
β-strand	462	1	9
β-strand	472-477	6	8
β-strand	483-485	3	7
α-helix	486-488	3
α-helix	493-497	5
α-helix	526-536	11
α-helix	545-553	9
α-helix	557-560	4
α-helix	562-564	3
α-helix	565-570	6
α-helix	577-588	12
α-helix	590-594	5
α-helix	595-598	4
α-helix	599-602	4
α-helix	609-622	14
α-helix	625-630	6
α-helix	632-637	6
α-helix	638-641	4
α-helix	648-659	12
α-helix	661-672	12
α-helix	681-692	12
α-helix	698-719	22
α-helix	728-739	12
α-helix	742-747	6
β-strand	751-753	3	11
β-strand	756-761	6	11
β-strand	764	1	12
β-strand	770-771	2	12
β-strand	779-784	6	12
β-strand	796-803	8	12
α-helix	808-826	19
β-strand	838-842	5	12
β-strand	845-849	5	12
β-strand	854-856	3	13
α-helix	857-860	4
α-helix	876-884	9
α-helix	888-911	24
α-helix	913-916	4
β-strand	921-924	4	13
β-strand	929-931	3	13
α-helix	941-944	4
α-helix	958-964	7
α-helix	971-973	3
α-helix	975-993	19
α-helix	995-1003	9
α-helix	1020-1025	6
α-helix	1032-1047	16

Chain B: 7 helices, 8 β-strands

Element	Residues	Length	Sheet
β-strand	334	1	14
α-helix	340-346	7
α-helix	350-351	2
β-strand	354-358	5	14
β-strand	369-374	6	14
β-strand	377-382	6	14
β-strand	384-386	3	15
β-strand	389-391	3	15
β-strand	398	1	15
α-helix	401-410	10
α-helix	413-415	3
β-strand	426-427	2	14
α-helix	430-433	4
α-helix	442-515	74
α-helix	518-587	70

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	A	protein	1074	Homo sapiens	P42336 (AlphaFold model)
Phosphatidylinositol 3-kinase regulatory subunit alpha	B	protein	293	Homo sapiens	P27986 (AlphaFold model)

Sequence of entity 1 (A), FASTA

>8SBC_1 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (chains A)
MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ
LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFA
IGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKH
IYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSKKLSSEQLK
LCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD
CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGI
YHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHC
PLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWF
SSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPL
SEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME
LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTN
QRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILK
QEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLK
LNWENPDIMSELLFQNNEIMFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLS
IGDCVGLIEWVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS
CAGYCVATFILGIGDRHNSNIMVKDDGQLVHIDFGHFLDHKKKKFGYKRERVPFVLTQDF
LIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIA
YIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALNHHHHHH

Sequence of entity 2 (B), FASTA

>8SBC_2 Phosphatidylinositol 3-kinase regulatory subunit alpha (chains B)
MHNLQYLPPKPPKPTTVANNGMNNNMSLQDAEWYWGDISREEVNEKLRDTADGTFLVRDA
STKMHGDYTLTLRKGGNNKLIKIFHRDGKYGFSDPLTFSSVVELINHYRNESLAQYNPKL
DVKLLYPVSKYQQDQVVKEDNIEAVGKKLHEYNTQFQEKSREYDRLYEEYTRTSQEIQMK
RTAIEAFNETIKIFEEQCQTQERYSKEYIEKFKREGNEKEIQRIMHNYDKLKSRISEIID
SRRRLEEDLKKQAAEYREIDKRMNSIKPDLIQLRKTRDQYLMWLTQKGVRQKK

Ligands and cofactors

ID	Name	Formula	Copies
ZTV	(2M)-7-[(3R)-3-methylmorpholin-4-yl]-5-[(3S)-3-methylmorpholin-4-yl]-2-(pyridin…	C21 H26 N6 O2	1

Water and common crystallization additives (SO4) are not listed.

Primary citation

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes. Bonazzi, S., Gray, A., Thomsen, N.M. et al. J Med Chem (2023) 66:9095-9119. DOI 10.1021/acs.jmedchem.3c00705 · PubMed

Other PDB entries of the same protein (UniProt P42336 (AlphaFold model), which also has an AlphaFold model), best resolution first:

9CMK 1.75 Å, Crystal structure of p110alpha-RAS binding domain (RBD) in complex with molecular glue…
9ASF 1.77 Å, Crystal structure of HLA-A*03:01 in complex with a wild-type PIK3CA peptide analogue…
9CX0 1.92 Å, Crystal structure of HLA-A*03:01 E152V mutant in complex with a mutant PIK3CA peptide
7L1C 1.96 Å, Crystal structure of HLA-A*03:01 in complex with a mutant PIK3CA peptide
9CWY 1.98 Å, Crystal structure of HLA-A*03:02 in complex with a wild-type PIK3CA peptide
8EXL 1.99 Å, Crystal structure of PI3K-alpha in complex with taselisib
9CX1 2.0 Å, Crystal structure of HLA-A*03:01 L156Q mutant in complex with a mutant PIK3CA peptide
9CML 2.01 Å, Crystal structure of p110alpha-RAS binding domain (RBD) in complex with molecular glue…
9ASG 2.03 Å, Crystal structure of HLA-A*03:01 in complex with a mutant PIK3CA peptide analogue (Trp-6…
7L1B 2.04 Å, Crystal structure of HLA-A*03:01 in complex with a wild-type PIK3CA peptide
9CWZ 2.05 Å, Crystal structure of HLA-A*03:02 in complex with a mutant PIK3CA peptide
7JIU 2.12 Å, Human PI3KDELTA in complex with compound 2F

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