9K95: Human gamma-secretase

Cryo-EM structure of human gamma-secretase in complex with compound E. Determined by electron microscopy at 2.9 Å resolution. Released 29 Oct 2025.

Method
Electron microscopy
Resolution
2.9 Å
Organism
Homo sapiens
Chains
4
Atoms
10,823
Mol. weight
179.84 kDa
Ligands
A1D6X, PC1, NAG, CLR
Released
29 Oct 2025

Explore 9K95 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

9K95 contains 62 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: 15 helices, 3 β-strands
ElementResiduesLengthSheet
α-helix83-10220
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
α-helix281-2833
β-strand287-28939
β-strand380-38239
α-helix383-39816
α-helix403-42826
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
NicastrinAprotein709Homo 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
>9K95_1 Nicastrin (chains A)
MATAGGGSGADPGSRGLLRLLSFCVLLAGLCRGNSVERKIYIPLNKTAPCVRLLNATHQI
GCQSSISGDTGVIHVVEKEEDLQWVLTDGPNPPYMVLLESKHFTRDLMEKLKGRTSRIAG
LAVSLTKPSPASGFSPSVQCPNDGFGVYSNSYGPEFAHCREIQWNSLGNGLAYEDFSFPI
FLLEDENETKVIKQCYQDHNLSQNGSAPTFPLCAMQLFSHMHAVISTATCMRRSSIQSTF
SINPEIVCDPLSDYNVWSMLKPINTTGTLKPDDRVVVAATRLDSRSFFWNVAPGAESAVA
SFVTQLAAAEALQKAPDVTTLPRNVMFVFFQGETFDYIGSSRMVYDMEKGKFPVQLENVD
SFVELGQVALRTSLELWMHTDPVSQKNESVRNQVEDLLATLEKSGAGVPAVILRRPNQSQ
PLPPSSLQRFLRARNISGVVLADHSGAFHNKYYQSIYDTAENINVSYPEWLSPEEDLNFV
TDTAKALADVATVLGRALYELAGGTNFSDTVQADPQTVTRLLYGFLIKANNSWFQSILRQ
DLRSYLGDGPLQHYIAVSSPTNTTYVVQYALANLTGTVVNLTREQCQDPSKVPSENKDLY
EYSWVQGPLHSNETDRLPRCVRSTARLARALSPAFELSQWSSTEYSTWTESRWKDIRARI
FLIASKELELITLTVGFGILIFSLIVTYCINAKADVLFIAPREPGAVSY
Sequence of entity 2 (B), FASTA
>9K95_2 Presenilin-1 (chains B)
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
Sequence of entity 3 (C), FASTA
>9K95_3 Gamma-secretase subunit APH-1A (chains C)
MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
RSLLCRRQEDSRVMVYSALRIPPED
Sequence of entity 4 (D), FASTA
>9K95_4 Gamma-secretase subunit PEN-2 (chains D)
MNLERVSNEEKLNLCRKYYLGGFAFLPFLWLVNIFWFFREAFLVPAYTEQSQIKGYVWRS
AVGFLFWVIVLTSWITIFQIYRPRWGALGDYLSFTIPLGTP

Ligands and cofactors

IDNameFormulaCopies
A1D6X(2~{S})-2-[2-[3,5-bis(fluoranyl)phenyl]ethanoylamino]-~{N}-[(3~{S})-1-methyl-2-…C27 H24 F2 N4 O31
PC11,2-diacyl-sn-glycero-3-phosphocholineC44 H88 N O8 P2
NAG2-acetamido-2-deoxy-beta-D-glucopyranoseC8 H15 N O66
CLRCholesterolC27 H46 O3

Primary citation

Structural insights into human signal peptide peptidase. Zhou, R., Huang, G., Guo, X. et al. To be published.

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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