6C4D: Structure based design of RIP1 kinase inhibitors

Structure based design of RIP1 kinase inhibitors. Determined by X-ray diffraction at 2.52 Å resolution. Released 21 Mar 2018.

Method: X-ray diffraction
Resolution: 2.52 Å
Organism: Homo sapiens
Chains: 4
Atoms: 8,649
Mol. weight: 136.23 kDa
Ligands: EJP
Released: 21 Mar 2018

Explore 6C4D in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

6C4D contains 60 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
β-strand	11-12	2	1
β-strand	31-35	5	1
β-strand	41-49	9	1
α-helix	58-68	11
β-strand	72	1	2
β-strand	75	1	2
α-helix	76-77	2
β-strand	78-83	6	1
β-strand	87-93	7	1
β-strand	98-99	2	2
α-helix	100-104	5
α-helix	109-111	3
α-helix	112-132	21
α-helix	141-143	3
β-strand	144-146	3	2
β-strand	152-154	3	2
α-helix	163-169	7
α-helix	190-192	3
α-helix	204-205	2
α-helix	207-223	17
α-helix	228-230	3
α-helix	235-242	8
α-helix	249-251	3
α-helix	258-267	10
α-helix	272-274	3
α-helix	278-288	11
α-helix	289-293	5

Chain B: 15 helices, 10 β-strands

Element	Residues	Length	Sheet
β-strand	10-12	3	3
α-helix	14-16	3
β-strand	17-22	6	3
β-strand	31-36	6	3
β-strand	40-48	9	3
α-helix	54-67	14
β-strand	75	1	4
β-strand	78-84	7	3
β-strand	87-93	7	3
β-strand	98-99	2	4
α-helix	100-104	5
α-helix	112-131	20
α-helix	141-143	3
β-strand	144-146	3	4
β-strand	152-154	3	4
α-helix	163-169	7
α-helix	195-197	3
α-helix	207-223	17
α-helix	234-243	10
α-helix	249-251	3
α-helix	258-267	10
α-helix	272-274	3
α-helix	276-277	2
α-helix	278-288	11
α-helix	289-293	5

Chain C: 16 helices, 10 β-strands

Element	Residues	Length	Sheet
β-strand	11-12	2	5
β-strand	21	1	5
β-strand	31-36	6	5
β-strand	40-46	7	5
α-helix	57-68	12
β-strand	75	1	6
α-helix	76-77	2
β-strand	78-84	7	5
β-strand	87-93	7	5
β-strand	98-99	2	6
α-helix	100-104	5
α-helix	109-111	3
α-helix	112-131	20
α-helix	141-143	3
β-strand	144-146	3	6
β-strand	152-154	3	6
α-helix	163-168	6
α-helix	203-205	3
α-helix	207-223	17
α-helix	234-242	9
α-helix	249-251	3
α-helix	258-267	10
α-helix	272-274	3
α-helix	276-277	2
α-helix	278-288	11
α-helix	289-293	5

Chain D: 12 helices, 13 β-strands

Element	Residues	Length	Sheet
α-helix	6-10	5
β-strand	11	1	7
β-strand	17	1	8
β-strand	31-32	2	7
β-strand	35-36	2	8
β-strand	40-41	2	8
β-strand	42-49	8	7
α-helix	58-68	11
β-strand	72	1	9
β-strand	75	1	9
β-strand	78-84	7	7
β-strand	87-93	7	7
β-strand	98-99	2	9
α-helix	100-105	6
α-helix	112-131	20
α-helix	141-143	3
β-strand	144-146	3	9
β-strand	152-154	3	9
α-helix	163-169	7
α-helix	204-205	2
α-helix	209-223	15
α-helix	235-242	8
α-helix	258-267	10
α-helix	276-277	2
α-helix	278-291	14

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Receptor-interacting serine/threonine-protein kinase 1	A, B, C, D	protein	297	Homo sapiens	Q13546 (AlphaFold model)

Sequence of entity 1 (A, B, C, D), FASTA

>6C4D_1 Receptor-interacting serine/threonine-protein kinase 1 (chains A, B, C, D)
GGSGQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLAFHRTQGLMIMKTVYKGPNCIEHN
EALLEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGR
IILEIIEGMAYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELR
EVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAIAEQQL
IMAIKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLE

Ligands and cofactors

ID	Name	Formula	Copies
EJP	(3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-…	C24 H20 Cl N5 O3	4

Primary citation

Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships. Yoshikawa, M., Saitoh, M., Katoh, T. et al. J Med Chem (2018) 61:2384-2409. DOI 10.1021/acs.jmedchem.7b01647 · PubMed

Other PDB entries of the same protein (UniProt Q13546 (AlphaFold model), which also has an AlphaFold model), best resolution first:

5ZMZ 1.4 Å, Amyloid core of RIP1
6AC5 1.45 Å, Crystal structure of RIPK1 death domain GlcNAcylated by EPEC effector NleB
4ITJ 1.8 Å, Crystal structure of RIP1 kinase in complex with necrostatin-4
6NW2 2.0 Å, Structure of human RIPK1 kinase domain in complex with compound 11
7FD0 2.0 Å, Crystal Structure of human RIPK1 kinase domain in complex with a novel inhibitor
24IB 2.05 Å, Crystal structure of human RIPK1 kinase domain in complex with compound HR10
9Q31 2.05 Å, RIP1 kinase domain in complex with GDC-8264
6NYH 2.1 Å, Structure of human RIPK1 kinase domain in complex with GNE684
9GTY 2.15 Å, RIPK1 in complex with AZ"320
7FCZ 2.21 Å, Crystal Structure of human RIPK1 kinase domain in complex with a novel inhibitor
5HX6 2.23 Å, Crystal structure of RIP1 kinase with a benzo[b][1,4]oxazepin-4-one
4ITH 2.25 Å, Crystal structure of RIP1 kinase in complex with necrostatin-1 analog

Browse structure collections

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