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Protein

Fizzy-related protein homolog

Gene

FZR1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:25349192).4 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processCell cycle, Cell division, DNA damage, DNA repair, Mitosis, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-174084 Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113 SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174178 APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-176407 Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase
R-HSA-176408 Regulation of APC/C activators between G1/S and early anaphase
R-HSA-176417 Phosphorylation of Emi1
R-HSA-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-HSA-69017 CDK-mediated phosphorylation and removal of Cdc6
R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SignaLinkiQ9UM11
SIGNORiQ9UM11
UniPathwayi
UPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
Fizzy-related protein homolog
Short name:
Fzr
Alternative name(s):
CDC20-like protein 1
Cdh1/Hct1 homolog
Short name:
hCDH1
Gene namesi
Name:FZR1
Synonyms:CDH1, FYR, FZR, KIAA1242
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000105325.13
HGNCiHGNC:24824 FZR1
MIMi603619 gene
neXtProtiNX_Q9UM11

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi40S → A: Constitutively active; when associated with A-121; A-151 and A-163. Does not affect APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-121; A-151 and A-163. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-121 and A-151. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-121 and A-163. 2 Publications1
Mutagenesisi47R → A: Inhibits APC/FZR1 E3 ubiquitin-protein ligase complex activity. 1 Publication1
Mutagenesisi52R → A: Inhibits APC/FZR1 E3 ubiquitin-protein ligase complex activity. 1 Publication1
Mutagenesisi121T → A: Constitutively active; when associated with A-40; A-151 and A-163. Does not affect APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-40; A-151 and A-163. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-40 and A-151. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-40 and A-163. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-151 and A-163. 2 Publications1
Mutagenesisi151S → A: Constitutively active; when associated with A-40; A-121 and A-163. Does not affect ubiquitination; when associated with A-40; A-121 and A-163. Decreases ubiquitination; when associated with A-40 and A-163. Decreases ubiquitination; when associated with A-121 and A-163. 2 Publications1
Mutagenesisi163S → A: Constitutively active; when associated with A-40; A-121 and A-151. Does not affect APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-40; A-121 and A-151. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-40 and A-121. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex activity; when associated with A-121 and A-151. Decreases ubiquitination; when associated with A-40 and A-151. 2 Publications1

Organism-specific databases

DisGeNETi51343
OpenTargetsiENSG00000105325
PharmGKBiPA134896003

Polymorphism and mutation databases

BioMutaiFZR1
DMDMi37537753

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000510011 – 496Fizzy-related protein homologAdd BLAST496

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei32PhosphothreonineCombined sources1
Modified residuei36PhosphoserineCombined sources1
Modified residuei69N6-acetyllysine1 Publication1
Modified residuei133PhosphoserineCombined sources1
Modified residuei138PhosphoserineCombined sources1
Modified residuei146PhosphoserineCombined sources1
Modified residuei151PhosphoserineCombined sources1
Modified residuei159N6-acetyllysine1 Publication1

Post-translational modificationi

Acetylated. Deacetylated by SIRT2 at Lys-69 and Lys-159; deacetylation enhances the interaction of FZR1 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).1 Publication
Phosphorylated during mitosis, probably by maturation promoting factor (MPF), leading to its dissociation of the APC/C. Following DNA damage, it is dephosphorylated by CDC14B in G2 phase, leading to its reassociation with the APC/C, and allowing an efficient G2 DNA damage checkpoint. Phosphorylated by MAK.3 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ9UM11
PaxDbiQ9UM11
PeptideAtlasiQ9UM11
PRIDEiQ9UM11
ProteomicsDBi85167
85168 [Q9UM11-2]
85169 [Q9UM11-3]

PTM databases

iPTMnetiQ9UM11
PhosphoSitePlusiQ9UM11

Expressioni

Tissue specificityi

Isoform 2 is expressed at high levels in heart, liver, spleen and some cancer cell lines whereas isoform 3 is expressed only at low levels in these tissues.1 Publication

Gene expression databases

BgeeiENSG00000105325 Expressed in 204 organ(s), highest expression level in testis
CleanExiHS_CDH1
ExpressionAtlasiQ9UM11 baseline and differential
GenevisibleiQ9UM11 HS

Organism-specific databases

HPAiHPA043536

Interactioni

Subunit structurei

The unphosphorylated form interacts with APC/C during mitosis (PubMed:26083744, PubMed:9734353). Interacts with NINL (PubMed:17403670). Interacts (in complex with the anaphase promoting complex APC) with MAD2L2; inhibits FZR1-mediated APC/C activation (PubMed:11459825, PubMed:11459826). Interacts with SIRT2 and USP37 (PubMed:21596315, PubMed:22014574). Interacts (via WD repeats) with MAK (PubMed:21986944). Interacts with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal degradation (PubMed:25349192). Interacts with HECW2 (PubMed:24163370).10 Publications

Binary interactionsi

Protein-protein interaction databases

BioGridi119489, 155 interactors
DIPiDIP-38700N
ELMiQ9UM11
IntActiQ9UM11, 39 interactors
MINTiQ9UM11
STRINGi9606.ENSP00000378529

Structurei

3D structure databases

ProteinModelPortaliQ9UM11
SMRiQ9UM11
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati182 – 222WD 1Add BLAST41
Repeati227 – 266WD 2Add BLAST40
Repeati269 – 306WD 3Add BLAST38
Repeati311 – 350WD 4Add BLAST40
Repeati353 – 395WD 5Add BLAST43
Repeati397 – 438WD 6Add BLAST42
Repeati441 – 480WD 7Add BLAST40

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni47 – 52Involved in APC/FZR1 E3 ubiquitin-protein ligase complex activity1 Publication6

Sequence similaritiesi

Belongs to the WD repeat CDC20/Fizzy family.Curated

Keywords - Domaini

Repeat, WD repeat

Phylogenomic databases

eggNOGiKOG0305 Eukaryota
ENOG410XQ8I LUCA
GeneTreeiENSGT00870000136444
HOVERGENiHBG001024
InParanoidiQ9UM11
KOiK03364
OMAiSVCSVQW
OrthoDBiEOG091G06FJ
PhylomeDBiQ9UM11
TreeFamiTF101066

Family and domain databases

Gene3Di2.130.10.10, 1 hit
InterProiView protein in InterPro
IPR024977 Apc4_WD40_dom
IPR033010 Cdc20/Fizzy
IPR015943 WD40/YVTN_repeat-like_dom_sf
IPR001680 WD40_repeat
IPR019775 WD40_repeat_CS
IPR017986 WD40_repeat_dom
IPR036322 WD40_repeat_dom_sf
PANTHERiPTHR19918 PTHR19918, 1 hit
PfamiView protein in Pfam
PF12894 ANAPC4_WD40, 1 hit
PF00400 WD40, 3 hits
SMARTiView protein in SMART
SM00320 WD40, 6 hits
SUPFAMiSSF50978 SSF50978, 1 hit
PROSITEiView protein in PROSITE
PS00678 WD_REPEATS_1, 2 hits
PS50082 WD_REPEATS_2, 3 hits
PS50294 WD_REPEATS_REGION, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 1 (identifier: Q9UM11-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MDQDYERRLL RQIVIQNENT MPRVTEMRRT LTPASSPVSS PSKHGDRFIP
60 70 80 90 100
SRAGANWSVN FHRINENEKS PSQNRKAKDA TSDNGKDGLA YSALLKNELL
110 120 130 140 150
GAGIEKVQDP QTEDRRLQPS TPEKKGLFTY SLSTKRSSPD DGNDVSPYSL
160 170 180 190 200
SPVSNKSQKL LRSPRKPTRK ISKIPFKVLD APELQDDFYL NLVDWSSLNV
210 220 230 240 250
LSVGLGTCVY LWSACTSQVT RLCDLSVEGD SVTSVGWSER GNLVAVGTHK
260 270 280 290 300
GFVQIWDAAA GKKLSMLEGH TARVGALAWN AEQLSSGSRD RMILQRDIRT
310 320 330 340 350
PPLQSERRLQ GHRQEVCGLK WSTDHQLLAS GGNDNKLLVW NHSSLSPVQQ
360 370 380 390 400
YTEHLAAVKA IAWSPHQHGL LASGGGTADR CIRFWNTLTG QPLQCIDTGS
410 420 430 440 450
QVCNLAWSKH ANELVSTHGY SQNQILVWKY PSLTQVAKLT GHSYRVLYLA
460 470 480 490
MSPDGEAIVT GAGDETLRFW NVFSKTRSTK VKWESVSVLN LFTRIR
Length:496
Mass (Da):55,179
Last modified:October 3, 2003 - v2
Checksum:iF6C8FDAF81D8103A
GO
Isoform 2 (identifier: Q9UM11-2) [UniParc]FASTAAdd to basket
Also known as: CDH1alpha, Fzr1

The sequence of this isoform differs from the canonical sequence as follows:
     481-483: Missing.

Note: Major.
Show »
Length:493
Mass (Da):54,766
Checksum:i7C6A947EBB8A6D5C
GO
Isoform 3 (identifier: Q9UM11-3) [UniParc]FASTAAdd to basket
Also known as: CDH1beta, Fzr2

The sequence of this isoform differs from the canonical sequence as follows:
     130-218: Missing.
     481-483: Missing.

Note: Minor.
Show »
Length:404
Mass (Da):44,874
Checksum:iA793194D88777035
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
K7EQT1K7EQT1_HUMAN
Fizzy-related protein homolog
FZR1
361Annotation score:

Sequence cautioni

The sequence AAD26623 differs from that shown. Contaminating sequence. Sequence of unknown origin in the C-terminal part.Curated
The sequence AAD26624 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated
The sequence BAA86556 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti259A → S in AAF20266 (Ref. 3) Curated1
Sequence conflicti275G → W in AAF20266 (Ref. 3) Curated1
Sequence conflicti326Q → H in BAA86954 (Ref. 2) Curated1
Sequence conflicti326Q → H in BAA86955 (Ref. 2) Curated1
Sequence conflicti341N → I in AAF20266 (Ref. 3) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_008503130 – 218Missing in isoform 3. 2 PublicationsAdd BLAST89
Alternative sequenceiVSP_008504481 – 483Missing in isoform 2 and isoform 3. 7 Publications3

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF102508 mRNA Translation: AAD26624.1 Sequence problems.
AF102507 mRNA Translation: AAD26623.1 Sequence problems.
AB013462 mRNA Translation: BAA86954.1
AB013463 mRNA Translation: BAA86955.1
AF080397 mRNA Translation: AAF20266.1
AF083810 mRNA Translation: AAD52030.1
AF433157 mRNA Translation: AAL28117.1
BT007115 mRNA Translation: AAP35779.1
AC005787 Genomic DNA Translation: AAC62835.1
AC005786 Genomic DNA Translation: AAC62836.1
AB033068 mRNA Translation: BAA86556.1 Different initiation.
BC013413 mRNA Translation: AAH13413.1
CCDSiCCDS12109.1 [Q9UM11-2]
CCDS45916.1 [Q9UM11-1]
CCDS45917.1 [Q9UM11-3]
RefSeqiNP_001129669.1, NM_001136197.1 [Q9UM11-3]
NP_001129670.1, NM_001136198.1 [Q9UM11-1]
NP_057347.2, NM_016263.3 [Q9UM11-2]
XP_005259630.1, XM_005259573.4 [Q9UM11-1]
UniGeneiHs.413133

Genome annotation databases

EnsembliENST00000313639; ENSP00000321800; ENSG00000105325 [Q9UM11-3]
ENST00000395095; ENSP00000378529; ENSG00000105325 [Q9UM11-1]
ENST00000441788; ENSP00000410369; ENSG00000105325 [Q9UM11-2]
GeneIDi51343
KEGGihsa:51343
UCSCiuc002lxt.3 human [Q9UM11-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF102508 mRNA Translation: AAD26624.1 Sequence problems.
AF102507 mRNA Translation: AAD26623.1 Sequence problems.
AB013462 mRNA Translation: BAA86954.1
AB013463 mRNA Translation: BAA86955.1
AF080397 mRNA Translation: AAF20266.1
AF083810 mRNA Translation: AAD52030.1
AF433157 mRNA Translation: AAL28117.1
BT007115 mRNA Translation: AAP35779.1
AC005787 Genomic DNA Translation: AAC62835.1
AC005786 Genomic DNA Translation: AAC62836.1
AB033068 mRNA Translation: BAA86556.1 Different initiation.
BC013413 mRNA Translation: AAH13413.1
CCDSiCCDS12109.1 [Q9UM11-2]
CCDS45916.1 [Q9UM11-1]
CCDS45917.1 [Q9UM11-3]
RefSeqiNP_001129669.1, NM_001136197.1 [Q9UM11-3]
NP_001129670.1, NM_001136198.1 [Q9UM11-1]
NP_057347.2, NM_016263.3 [Q9UM11-2]
XP_005259630.1, XM_005259573.4 [Q9UM11-1]
UniGeneiHs.413133

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4UI9electron microscopy3.60R1-496[»]
5L9Telectron microscopy6.40R1-496[»]
5L9Uelectron microscopy6.40R1-496[»]
ProteinModelPortaliQ9UM11
SMRiQ9UM11
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119489, 155 interactors
DIPiDIP-38700N
ELMiQ9UM11
IntActiQ9UM11, 39 interactors
MINTiQ9UM11
STRINGi9606.ENSP00000378529

PTM databases

iPTMnetiQ9UM11
PhosphoSitePlusiQ9UM11

Polymorphism and mutation databases

BioMutaiFZR1
DMDMi37537753

Proteomic databases

EPDiQ9UM11
PaxDbiQ9UM11
PeptideAtlasiQ9UM11
PRIDEiQ9UM11
ProteomicsDBi85167
85168 [Q9UM11-2]
85169 [Q9UM11-3]

Protocols and materials databases

DNASUi51343
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000313639; ENSP00000321800; ENSG00000105325 [Q9UM11-3]
ENST00000395095; ENSP00000378529; ENSG00000105325 [Q9UM11-1]
ENST00000441788; ENSP00000410369; ENSG00000105325 [Q9UM11-2]
GeneIDi51343
KEGGihsa:51343
UCSCiuc002lxt.3 human [Q9UM11-1]

Organism-specific databases

CTDi51343
DisGeNETi51343
EuPathDBiHostDB:ENSG00000105325.13
GeneCardsiFZR1
HGNCiHGNC:24824 FZR1
HPAiHPA043536
MIMi603619 gene
neXtProtiNX_Q9UM11
OpenTargetsiENSG00000105325
PharmGKBiPA134896003
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0305 Eukaryota
ENOG410XQ8I LUCA
GeneTreeiENSGT00870000136444
HOVERGENiHBG001024
InParanoidiQ9UM11
KOiK03364
OMAiSVCSVQW
OrthoDBiEOG091G06FJ
PhylomeDBiQ9UM11
TreeFamiTF101066

Enzyme and pathway databases

UniPathwayi
UPA00143

ReactomeiR-HSA-174084 Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113 SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174178 APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-176407 Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase
R-HSA-176408 Regulation of APC/C activators between G1/S and early anaphase
R-HSA-176417 Phosphorylation of Emi1
R-HSA-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-HSA-69017 CDK-mediated phosphorylation and removal of Cdc6
R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SignaLinkiQ9UM11
SIGNORiQ9UM11

Miscellaneous databases

ChiTaRSiFZR1 human
GeneWikiiFZR1
GenomeRNAii51343
PROiPR:Q9UM11
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000105325 Expressed in 204 organ(s), highest expression level in testis
CleanExiHS_CDH1
ExpressionAtlasiQ9UM11 baseline and differential
GenevisibleiQ9UM11 HS

Family and domain databases

Gene3Di2.130.10.10, 1 hit
InterProiView protein in InterPro
IPR024977 Apc4_WD40_dom
IPR033010 Cdc20/Fizzy
IPR015943 WD40/YVTN_repeat-like_dom_sf
IPR001680 WD40_repeat
IPR019775 WD40_repeat_CS
IPR017986 WD40_repeat_dom
IPR036322 WD40_repeat_dom_sf
PANTHERiPTHR19918 PTHR19918, 1 hit
PfamiView protein in Pfam
PF12894 ANAPC4_WD40, 1 hit
PF00400 WD40, 3 hits
SMARTiView protein in SMART
SM00320 WD40, 6 hits
SUPFAMiSSF50978 SSF50978, 1 hit
PROSITEiView protein in PROSITE
PS00678 WD_REPEATS_1, 2 hits
PS50082 WD_REPEATS_2, 3 hits
PS50294 WD_REPEATS_REGION, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiFZR1_HUMAN
AccessioniPrimary (citable) accession number: Q9UM11
Secondary accession number(s): O75869
, Q86U66, Q96NW8, Q9UI96, Q9ULH8, Q9UM10, Q9UNQ1, Q9Y2T8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 3, 2003
Last sequence update: October 3, 2003
Last modified: October 10, 2018
This is version 179 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  4. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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