8KCT: Human gamma-secretase

Cryo-EM structure of human gamma-secretase in complex with Nirogacestat. Determined by electron microscopy at 2.6 Å resolution. Released 14 Aug 2024.

Method
Electron microscopy
Resolution
2.6 Å
Organism
Homo sapiens
Chains
4
Atoms
10,839
Mol. weight
178.98 kDa
Ligands
NAG, PC1, O6U, CLR
Released
14 Aug 2024

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

Secondary structure: helices and β-sheets

8KCT contains 61 α-helices and 34 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, 29 β-strands

ElementResiduesLengthSheet
α-helix37-393
β-strand42-4431
β-strand47-4931
β-strand53-5422
β-strand59-6022
β-strand6113
β-strand69-7681
α-helix80-834
α-helix84-885
β-strand94-9961
α-helix105-1128
β-strand118-12471
β-strand13514
α-helix154-1563
β-strand16814
α-helix171-1733
β-strand17513
β-strand180-18341
α-helix186-19914
α-helix207-2093
β-strand212-21871
α-helix227-24014
β-strand248-25032
β-strand253-25975
β-strand275-28175
α-helix295-2995
α-helix300-31314
β-strand324-33075
α-helix338-34811
α-helix356-3583
β-strand359-36575
β-strand375-37955
α-helix384-3863
α-helix388-40518
β-strand412-41435
α-helix422-4232
α-helix427-4304
β-strand437-44265
α-helix473-4775
α-helix479-4813
α-helix482-50120
α-helix515-52612
α-helix540-5456
α-helix550-5523
α-helix562-57514
β-strand577-57936
α-helix583-5875
α-helix589-5913
β-strand60117
β-strand604-60526
α-helix608-6103
β-strand619-62246
β-strand62317
β-strand626-63055
α-helix633-6364
β-strand649-65132
β-strand657-66371
α-helix666-69227
α-helix694-6974
Chain B: 14 helices, 3 β-strands
ElementResiduesLengthSheet
α-helix83-10321
α-helix125-15531
α-helix159-17113
α-helix172-1776
α-helix178-18912
β-strand193-19428
α-helix195-21420
α-helix219-23921
α-helix243-26220
α-helix267-27711
β-strand287-28939
β-strand380-38239
α-helix383-39816
α-helix405-42824
α-helix435-44814
α-helix449-4535
α-helix454-4629
Chain C: 12 helices, 1 β-strand
ElementResiduesLengthSheet
α-helix3-1311
α-helix15-206
α-helix21-255
α-helix29-6032
α-helix65-10238
α-helix114-13926
β-strand14611
α-helix156-18328
α-helix187-20216
α-helix203-2053
α-helix210-2123
α-helix215-23117
α-helix236-2405
Chain D: 5 helices, 1 β-strand
ElementResiduesLengthSheet
α-helix8-2114
α-helix27-3610
α-helix39-424
α-helix50-8031
α-helix88-914
β-strand93-9538

Molecules and chains

MoleculeChainsTypeLengthOrganismUniProt
NicastrinAprotein701Homo sapiensQ92542 (AlphaFold model)
Gamma-secretase subunit APH-1ACprotein265Homo sapiensQ96BI3 (AlphaFold model)
Gamma-secretase subunit PEN-2Dprotein101Homo sapiensQ9NZ42 (AlphaFold model)
Presenilin-1Bprotein467Homo sapiensP49768 (AlphaFold model)
Sequence of entity 1 (A), FASTA
>8KCT_1 Nicastrin (chains A)
MATAGGGSGADPGSRGLLRLLSFCVLLAGLCRGNSVERKIYIPLNKTAPCVRLLNATHQI
GCQSSISGDTGVIHVVEKEEDLQWVLTDGPNPPYMVLLESKHFTRDLMEKLKGRTSRIAG
LAVSLTKPSPASGFSPSVQCPNDGFGVYSNSYGPEFAHCREIQWNSLGNGLAYEDFSFPI
FLLEDENETKVIKQCYQDHNLSQNGSAPTFPLCAMQLFSHMHAVISTATCMRRSSIQSTF
SINPEIVCDPLSDYNVWSMLKPINTTGTLKPDDRVVVAATRLDSRSFFWNVAPGAESAVA
SFVTQLAAAEALQKAPDVTTLPRNVMFVFFQGETFDYIGSSRMVYDMEKGKFPVQLENVD
SFVELGQVALRTSLELWMHTDPVSQKNESVRNQVEDLLATLEKSGAGVPAVILRRPNQSQ
PLPPSSLQRFLRARNISGVVLADHSGAFHNKYYQSIYDTAENINVSYPEWLSPEEDLNFV
TDTAKALADVATVLGRALYELAGGTNFSDTVQADPQTVTRLLYGFLIKANNSWFQSILRQ
DLRSYLGDGPLQHYIAVSSPTNTTYVVQYALANLTGTVVNLTREQCQDPSKVPSENKDLY
EYSWVQGPLHSNETDRLPRCVRSTARLARALSPAFELSQWSSTEYSTWTESRWKDIRARI
FLIASKELELITLTVGFGILIFSLIVTYCINAKADVLFIAP
Sequence of entity 2 (C), FASTA
>8KCT_2 Gamma-secretase subunit APH-1A (chains C)
MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
RSLLCRRQEDSRVMVYSALRIPPED
Sequence of entity 3 (D), FASTA
>8KCT_3 Gamma-secretase subunit PEN-2 (chains D)
MNLERVSNEEKLNLCRKYYLGGFAFLPFLWLVNIFWFFREAFLVPAYTEQSQIKGYVWRS
AVGFLFWVIVLTSWITIFQIYRPRWGALGDYLSFTIPLGTP
Sequence of entity 4 (B), FASTA
>8KCT_4 Presenilin-1 (chains B)
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI

Ligands and cofactors

IDNameFormulaCopies
NAG2-acetamido-2-deoxy-beta-D-glucopyranoseC8 H15 N O66
PC11,2-diacyl-sn-glycero-3-phosphocholineC44 H88 N O8 P2
O6UNirogacestatC27 H41 F2 N5 O1
CLRCholesterolC27 H46 O3

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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