8KCO: Human gamma-secretase

Cryo-EM structure of human gamma-secretase in complex with RO4929097. Determined by electron microscopy at 2.8 Å resolution. Released 14 Aug 2024.

Method
Electron microscopy
Resolution
2.8 Å
Organism
Homo sapiens
Chains
4
Atoms
10,837
Mol. weight
178.96 kDa
Ligands
CLR, PC1, N60, NAG
Released
14 Aug 2024

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

Secondary structure: helices and β-sheets

8KCO contains 61 α-helices and 32 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: 30 helices, 27 β-strands

ElementResiduesLengthSheet
α-helix37-393
β-strand42-4321
β-strand47-4931
β-strand53-5422
β-strand59-6022
β-strand6113
α-helix64-652
β-strand69-7571
α-helix81-833
α-helix84-885
β-strand94-9961
α-helix100-1023
α-helix105-1139
β-strand118-12471
α-helix125-1262
β-strand13514
β-strand16814
α-helix171-1733
β-strand17513
β-strand180-18341
α-helix186-19914
α-helix207-2093
β-strand212-21871
α-helix227-23913
β-strand248-25032
β-strand253-25975
β-strand275-28175
α-helix295-2995
α-helix300-31314
β-strand324-33075
α-helix338-34811
β-strand359-36575
β-strand375-37955
α-helix384-3863
α-helix388-40518
β-strand412-41435
α-helix427-4304
β-strand437-44265
α-helix473-4764
α-helix482-50221
α-helix515-52612
α-helix532-5354
α-helix540-5456
α-helix550-5523
α-helix562-57514
β-strand577-57936
α-helix583-5875
α-helix589-5913
β-strand601-60556
β-strand619-62356
β-strand626-63055
α-helix633-6364
β-strand649-65132
α-helix6521
β-strand657-66371
α-helix666-69227
α-helix694-6974
Chain B: 14 helices, 3 β-strands
ElementResiduesLengthSheet
α-helix80-10223
α-helix125-15531
α-helix159-17113
α-helix172-1776
α-helix178-18811
β-strand193-19427
α-helix195-21420
α-helix219-23921
α-helix243-26220
α-helix267-27610
β-strand288-28928
β-strand380-38128
α-helix383-39816
α-helix405-42824
α-helix436-44712
α-helix448-4536
α-helix454-46310
Chain C: 12 helices, 1 β-strand
ElementResiduesLengthSheet
α-helix3-2018
α-helix21-255
α-helix29-6032
α-helix66-9934
α-helix100-1045
α-helix114-13421
α-helix139-1413
β-strand14611
α-helix156-18429
α-helix188-20316
α-helix210-2123
α-helix215-23117
α-helix236-2405
Chain D: 5 helices, 1 β-strand
ElementResiduesLengthSheet
α-helix8-2114
α-helix27-3610
α-helix38-414
α-helix50-8132
α-helix88-914
β-strand93-9537

Molecules and chains

MoleculeChainsTypeLengthOrganismUniProt
NicastrinAprotein701Homo sapiensQ92542 (AlphaFold model)
Presenilin-1Bprotein467Homo sapiensP49768 (AlphaFold model)
Gamma-secretase subunit APH-1ACprotein265Homo sapiensQ96BI3 (AlphaFold model)
Gamma-secretase subunit PEN-2Dprotein101Homo sapiensQ9NZ42 (AlphaFold model)
Sequence of entity 1 (A), FASTA
>8KCO_1 Nicastrin (chains A)
MATAGGGSGADPGSRGLLRLLSFCVLLAGLCRGNSVERKIYIPLNKTAPCVRLLNATHQI
GCQSSISGDTGVIHVVEKEEDLQWVLTDGPNPPYMVLLESKHFTRDLMEKLKGRTSRIAG
LAVSLTKPSPASGFSPSVQCPNDGFGVYSNSYGPEFAHCREIQWNSLGNGLAYEDFSFPI
FLLEDENETKVIKQCYQDHNLSQNGSAPTFPLCAMQLFSHMHAVISTATCMRRSSIQSTF
SINPEIVCDPLSDYNVWSMLKPINTTGTLKPDDRVVVAATRLDSRSFFWNVAPGAESAVA
SFVTQLAAAEALQKAPDVTTLPRNVMFVFFQGETFDYIGSSRMVYDMEKGKFPVQLENVD
SFVELGQVALRTSLELWMHTDPVSQKNESVRNQVEDLLATLEKSGAGVPAVILRRPNQSQ
PLPPSSLQRFLRARNISGVVLADHSGAFHNKYYQSIYDTAENINVSYPEWLSPEEDLNFV
TDTAKALADVATVLGRALYELAGGTNFSDTVQADPQTVTRLLYGFLIKANNSWFQSILRQ
DLRSYLGDGPLQHYIAVSSPTNTTYVVQYALANLTGTVVNLTREQCQDPSKVPSENKDLY
EYSWVQGPLHSNETDRLPRCVRSTARLARALSPAFELSQWSSTEYSTWTESRWKDIRARI
FLIASKELELITLTVGFGILIFSLIVTYCINAKADVLFIAP
Sequence of entity 2 (B), FASTA
>8KCO_2 Presenilin-1 (chains B)
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
Sequence of entity 3 (C), FASTA
>8KCO_3 Gamma-secretase subunit APH-1A (chains C)
MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
RSLLCRRQEDSRVMVYSALRIPPED
Sequence of entity 4 (D), FASTA
>8KCO_4 Gamma-secretase subunit PEN-2 (chains D)
MNLERVSNEEKLNLCRKYYLGGFAFLPFLWLVNIFWFFREAFLVPAYTEQSQIKGYVWRS
AVGFLFWVIVLTSWITIFQIYRPRWGALGDYLSFTIPLGTP

Ligands and cofactors

IDNameFormulaCopies
CLRCholesterolC27 H46 O3
PC11,2-diacyl-sn-glycero-3-phosphocholineC44 H88 N O8 P2
N602,2-dimethyl-N-[(7S)-6-oxo-5,7-dihydrobenzo[d][1]benzazepin-7-yl]-N'-(2,2,3,3,3…C22 H20 F5 N3 O31
NAG2-acetamido-2-deoxy-beta-D-glucopyranoseC8 H15 N O66

Primary citation

Structural basis of human gamma-secretase inhibition by anticancer clinical compounds. Guo, X., Li, H., Lu, X. et al. Nat Struct Mol Biol (2025) 32:719-728. DOI 10.1038/s41594-024-01439-8 · PubMed

Other PDB entries of the same protein (UniProt Q92542 (AlphaFold model), which also has an AlphaFold model), best resolution first:

Browse structure collections

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