Structure of yeast 20S open-gate proteasome with Compound 24

Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

Macropain subunit Y7, Multicatalytic endopeptidase complex subunit Y7, Proteinase YSCE subunit 7

Macropain subunit Y13, Multicatalytic endopeptidase complex subunit Y13, Proteinase YSCE subunit 13

Macropain subunit PRE6, Multicatalytic endopeptidase complex subunit PRE6, Proteinase YSCE subunit PRE6

Macropain subunit PUP2, Multicatalytic endopeptidase complex subunit PUP2, Proteinase YSCE subunit PUP2

Macropain subunit PRE5, Multicatalytic endopeptidase complex subunit PRE5, Proteinase YSCE subunit PRE5

Macropain subunit C1, Multicatalytic endopeptidase complex subunit C1, Proteinase YSCE subunit 1

Macropain subunit C7-alpha, Multicatalytic endopeptidase complex C7, Proteasome component Y8, Proteinase YSCE subunit 7, SCL1 suppressor protein

Macropain subunit PUP1, Multicatalytic endopeptidase complex subunit PUP1, Proteinase YSCE subunit PUP1

Macropain subunit PUP3, Multicatalytic endopeptidase complex subunit PUP3

Macropain subunit C11, Multicatalytic endopeptidase complex subunit C11, Proteinase YSCE subunit 11

Macropain subunit PRE2, Multicatalytic endopeptidase complex subunit PRE2, Proteinase YSCE subunit PRE2

Multicatalytic endopeptidase complex subunit C5

Macropain subunit PRE4, Multicatalytic endopeptidase complex subunit PRE4, Proteinase YSCE subunit PRE4

Macropain subunit PRE3, Multicatalytic endopeptidase complex subunit PRE3, Proteinase YSCE subunit PRE3

MTDRYSFSLTTFSPSGKLGQIDYALTAVKQGVTSLGIKATNGVVIATEKKSSSPLAMSETLSKVSLLTPDIGAVYSGMGP
DYRVLVDKSRKVAHTSYKRIYGEYPPTKLLVSEVAKIMQEATQSGGVRPFGVSLLIAGHDEFNGFSLYQVDPSGSYFPWK
ATAIGKGSVAAKTFLEKRWNDELELEDAIHIALLTLKESVEGEFNGDTIELAIIGDENPDLLGYTGIPTDKGPRFRKLTS
QEINDRLEAL

TIFSPEGRLYQVEYALESISHAGTAIGIMASDGIVLAAERKVTSTLLEQDTSTEKLYKLNDKIAVAVAGLTADAEILINT
ARIHAQNYLKTYNEDIPVEILVRRLSDIKQGYTQHGGLRPFGVSFIYAGYDDRYGYQLYTSNPSGNYTGWKAISVGANTS
AAQTLLQMDYKDDMKVDDAIELALKTLSKTTDSSALTYDRLEFATIRKGANDGEVYQKIFKPQEIKDILVKTGIT

GYDRALSIFSPDGHIFQVEYALEAVKRGTCAVGVKGKNCVVLGCERRSTLKLQDTRITPSKVSKIDSHVVLSFSGLNADS
RILIEKARVEAQSHRLTLEDPVTVEYLTRYVAGVQQRYTQSGGVRPFGVSTLIAGFDPRDDEPKLYQTEPSGIYSSWSAQ
TIGRNSKTVREFLEKNYDRKEPPATVEECVKLTVRSLLEVVQTGAKNIEITVVKPDSDIVALSSEEINQYVTQIEQEKQE
Q

MFLTRSEYDRGVSTFSPEGRLFQVEYSLEAIKLGSTAIGIATKEGVVLGVEKRATSPLLESDSIEKIVEIDRHIGCAMSG
LTADARSMIEHARTAAVTHNLYYDEDINVESLTQSVCDLALRFGEGASGEERLMSRPFGVALLIAGHDADDGYQLFHAEP
SGTFYRYNAKAIGSGSEGAQAELLNEWHSSLTLKEAELLVLKILKQVMEEKLDENNAQLSCITKQDGFKIYDNEKTAELI
KELKEKEAAESPEEADVEMS

FRNNYDGDTVTFSPTGRLFQVEYALEAIKQGSVTVGLRSNTHAVLVALKRNADELSSYQKKIIKCDEHMGLSLAGLAPDA
RVLSNYLRQQCNYSSLVFNRKLAVERAGHLLCDKAQKNTQSYGGRPYGVGLLIIGYDKSGAHLLEFQPSGNVTELYGTAI
GARSQGAKTYLERTLDTFIKIDGNPDELIKAGVEAISQSLRDESLTVDNLSIAIVGKDTPFTIYDGEAVAKYI

GYDLSNSVFSPDGRNFQVEYAVKAVENGTTSIGIKCNDGVVFAVEKLITSKLLVPQKNVKIQVVDRHIGCVYSGLIPDGR
HLVNRGREEAASFKKLYKTPIPIPAFADRLGQYVQAHTLYNSVRPFGVSTIFGGVDKNGAHLYMLEPSGSYWGYKGAATG
KGRQSAKAELEKLVDHHPEGLSAREAVKQAAKIIYLAHEDNKEKDFELEISWCSLSETNGLHKFVKGDLLQEAIDFAQKE
IN

AGYDRHITIFSPEGRLYQVEYAFKATNQTNINSLAVRGKDCTVVISQKKVPDKLLDPTTVSYIFCISRTIGMVVNGPIPD
ARNAALRAKAEAAEFRYKYGYDMPCDVLAKRMANLSQIYTQRAYMRPLGVILTFVSVDEELGPSIYKTDPAGYYVGYKAT
ATGPKQQEITTNLENHFKKSKIDHINEESWEKVVEFAITHMIDALGTEFSKNDLEVGVATKDKFFTLSAENIEERLVAIA
EQD

TTIVGVKFNNGVVIAADTRSTQGPIVADKNCAKLHRISPKIWCAGAGTAADTEAVTQLIGSNIELHSLYTSREPRVVSAL
QMLKQHLFKYQGHIGAYLIVAGVDPTGSHLFSIHAHGSTDVGYYLSLGSGSLAAMAVLESHWKQDLTKEEAIKLASDAIQ
AGIWNDLGSGSNVDVCVMEIGKDAEYLRNYLTPNVREEKQKSYKFPRGTTAVLKESIVNICD

SDPSSINGGIVVAMTGKDCVAIACDLRLGSQSLGVSNKFEKIFHYGHVFLGITGLATDVTTLNEMFRYKTNLYKLKEERA
IEPETFTQLVSSSLYERRFGPYFVGPVVAGINSKSGKPFIAGFDLIGCIDEAKDFIVSGTASDQLFGMCESLYEPNLEPE
DLFETISQALLNAADRDALSGWGAVVYIIKKDEVVKRYLKMRQD

MDIILGIRVQDSVILASSKAVTRGISVLKDSDDKTRQLSPHTLMSFAGEAGDTVQFAEYIQANIQLYSIREDYELSPQAV
SSFVRQELAKSIRSRRPYQVNVLIGGYDKKKNKPELYQIDYLGTKVELPYGAHGYSGFYTFSLLDHHYRPDMTTEEGLDL
LKLCVQELEKRMPMDFKGVIVKIVDKDGIRQVDDFQAQ

TTTLAFRFQGGIIVAVDSRATAGNWVASQTVKKVIEINPFLLGTMAGGAADCQFWETWLGSQCRLHELREKERISVAAAS
KILSNLVYQYKGAGLSMGTMICGYTRKEGPTIYYVDSDGTRLKGDIFCVGSGQTFAYGVLDSNYKWDLSVEDALYLGKRS
ILAAAHRDAYSGGSVNLYHVTEDGWIYHGNHDVGELFWKVKEEEGSFNNVIG

QFNPYGDNGGTILGIAGEDFAVLAGDTRNITDYSINSRYEPKVFDCGDNIVMSANGFAADGDALVKRFKNSVKWYHFDHN
DKKLSINSAARNIQHLLYGKRFFPYYVHTIIAGLDEDGKGAVYSFDPVGSYEREQCRAGGAAASLIMPFLDNQVNFKNQY
EPGTNGKVKKPLKYLSVEEVIKLVRDSFTSATERHIQVGDGLEILIVTKDGVRKEFYELKRD

TQQPIVTGTSVISMKYDNGVIIAADNLGSYGSLLRFNGVERLIPVGDNTVVGISGDISDMQHIERLLKDLVTENAYDNPL
ADAEEALEPSYIFEYLATVMYQRRSKMNPLWNAIIVAGVQSNGDQFLRYVNLLGVTYSSPTLATGFGAHMANPLLRKVVD
RESDIPKTTVQVAEEAIVNAMRVLYYRDARSSRNFSLAIIDKNTGLTFKKNLQVENMKWDFAKDIKGYGTQKI

TSIMAVTFKDGVILGADSRTTTGAYIANRVTDKLTRVHDKIWCCRSGSAADTQAIADIVQYHLELYTSQYGTPSTETAAS
VFKELCYENKDNLTAGIIVAGYDDKNKGEVYTIPLGGSVHKLPYAIAGSGSTFIYGYCDKNFRENMSKEETVDFIKHSLS
QAIKWDGSSGGVIRMVVLTAAGVERLIFYPDEYEQL

100 mM MES, pH 7.0, 40 mM MgOAc, 15% 2-methyl-2,4-pentanediol (MPD), 10 mM EDTA, vapor diffusion, hanging drop, temperature 293K

OEU IS A NON-COVALENT DI-PEPTIDE SELECTIVE INHIBITOR OF THE HUMAN 20S PROTEASONE BETA5-SUBUNIT

HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
20S proteasome, Hydrolase-Hydrolase Inhibitor complex