spacer
spacer

PDBsum entry 1r4n
Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Cell cycle PDB id
1r4n

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
516 a.a. *
418 a.a. *
76 a.a. *
Ligands
ATP ×4
Metals
_ZN ×4
* Residue conservation analysis
PDB id:
1r4n
Name: Cell cycle
Title: Appbp1-uba3-nedd8, an e1-ubiquitin-like protein complex with atp
Structure: Amyloid beta precursor protein-binding protein 1. Chain: a, c, e, g. Synonym: appbp1. Engineered: yes. Ubiquitin-activating enzyme e1c. Chain: b, d, f, h. Synonym: uba3. Engineered: yes. Mutation: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: nedd8. Expression_system_taxid: 562
Biol. unit: Trimer (from PQS)
Resolution:
3.60Å     R-factor:   0.251     R-free:   0.290
Authors: H.Walden,M.S.Podgorski,J.M.Holton,B.A.Schulman
Key ref:
H.Walden et al. (2003). The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1. Mol Cell, 12, 1427-1437. PubMed id: 14690597 DOI: 10.1016/S1097-2765(03)00452-0
Date:
07-Oct-03     Release date:   23-Dec-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q13564  (ULA1_HUMAN) -  NEDD8-activating enzyme E1 regulatory subunit from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		534 a.a.
516 a.a.
Protein chains
Pfam   ArchSchema ?
Q8TBC4  (UBA3_HUMAN) -  NEDD8-activating enzyme E1 catalytic subunit from Homo sapiens
Seq:
Struc: 		463 a.a.
418 a.a.*
Protein chains
Pfam   ArchSchema ?
Q15843  (NEDD8_HUMAN) -  NEDD8 from Homo sapiens
Seq:
Struc: 		81 a.a.
76 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains B, D, F, H: E.C.6.2.1.64  - E1 NEDD8-activating enzyme.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [NEDD8 protein] + [E1 NEDD8-activating enzyme]-L-cysteine = AMP + diphosphate + [E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L- cysteine
ATP
Bound ligand (Het Group name = ATP)
corresponds exactly 		+ [NEDD8 protein]
 + [E1 NEDD8-activating enzyme]-L-cysteine
 = AMP
 + diphosphate
 + [E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L- cysteine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1016/S1097-2765(03)00452-0 Mol Cell 12:1427-1437 (2003)
PubMed id: 14690597  
 
 
The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1.
H.Walden, M.S.Podgorski, D.T.Huang, D.W.Miller, R.J.Howard, D.L.Minor, J.M.Holton, B.A.Schulman.
 
  ABSTRACT  
 
E1 enzymes initiate ubiquitin-like protein (ubl) transfer cascades by catalyzing adenylation of the ubl's C terminus. An E1's selectivity for its cognate ubl is essential because the E1 subsequently coordinates the ubl with its correct downstream pathway. We report here the structure of the 120 kDa quaternary complex between human APPBP1-UBA3, a heterodimeric E1, its ubl NEDD8, and ATP. The E1 selectively recruits NEDD8 through a bipartite interface, involving a domain common to all ubl activating enzymes including bacterial ancestors, and also eukaryotic E1-specific sequences. By modeling ubiquitin into the NEDD8 binding site and performing mutational analysis, we identify a single conserved arginine in APPBP1-UBA3 that acts as a selectivity gate, preventing misactivation of ubiquitin by NEDD8's E1. NEDD8 residues that interact with E1 correspond to residues in ubiquitin important for binding the proteasome and other ubiquitin-interacting proteins, suggesting that the conjugation and recognition machineries have coevolved for each specific ubl.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Stereo Views of Electron Density Maps(A) NEDD8 displayed in the initial NCS-averaged 2Fo-Fc map contoured at 1.5σ, calculated from the original model lacking NEDD8.(B) Detail from the final refined 2Fo-Fc map showing NEDD8 interaction with UBA3 contoured at 1.5σ. 		Figure 2.
Figure 2. Overall Structure of the APPBP1-UBA3-NEDD8-ATP ComplexThree views of the complex are shown in cartoon (top) and space-filling representations (bottom), each view a 35°â€“55° rotation around the y axis as indicated. APPBP1 is shown in blue, UBA3 in red, NEDD8 in yellow, and the position of the catalytic cysteine (C216A here) in green. The location of ATP is indicated in each view in the cartoon representations. The adenylation domain, the catalytic cysteine domain, and the C-terminal domain (CTD) are indicated. Figures were made using Pymol (DeLano, 2002).
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 12, 1427-1437) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23142976 S.E.Kaiser, K.Mao, A.M.Taherbhoy, S.Yu, J.L.Olszewski, D.M.Duda, I.Kurinov, A.Deng, T.D.Fenn, D.J.Klionsky, and B.A.Schulman (2012).
Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures.
  Nat Struct Mol Biol, 19, 1242-1249.
PDB codes: 4gsj 4gsk 4gsl
21240405 C.H.Leung, D.S.Chan, H.Yang, R.Abagyan, S.M.Lee, G.Y.Zhu, W.F.Fong, and D.L.Ma (2011).
A natural product-like inhibitor of NEDD8-activating enzyme.
  Chem Commun (Camb), 47, 2511-2513.  
21311953 S.K.Hotton, R.A.Eigenheer, M.F.Castro, M.Bostick, and J.Callis (2011).
AXR1-ECR1 and AXL1-ECR1 heterodimeric RUB-activating enzymes diverge in function in Arabidopsis thaliana.
  Plant Mol Biol, 75, 515-526.  
20396627 G.Brahemi, A.M.Burger, A.D.Westwell, and A.Brancale (2010).
Homology Modelling of Human E1 Ubiquitin Activating Enzyme.
  Lett Drug Des Discov, 7, 57-62.  
20129059 J.E.Brownell, M.D.Sintchak, J.M.Gavin, H.Liao, F.J.Bruzzese, N.J.Bump, T.A.Soucy, M.A.Milhollen, X.Yang, A.L.Burkhardt, J.Ma, H.K.Loke, T.Lingaraj, D.Wu, K.B.Hamman, J.J.Spelman, C.A.Cullis, S.P.Langston, S.Vyskocil, T.B.Sells, W.D.Mallender, I.Visiers, P.Li, C.F.Claiborne, M.Rolfe, J.B.Bolen, and L.R.Dick (2010).
Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ.
  Mol Cell, 37, 102-111.
PDB code: 3gzn
20368332 J.P.Bacik, J.R.Walker, M.Ali, A.D.Schimmer, and S.Dhe-Paganon (2010).
Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme.
  J Biol Chem, 285, 20273-20280.
PDB code: 3h8v
21209884 J.Wang, A.M.Taherbhoy, H.W.Hunt, S.N.Seyedin, D.W.Miller, D.J.Miller, D.T.Huang, and B.A.Schulman (2010).
Crystal structure of UBA2(ufd)-Ubc9: insights into E1-E2 interactions in Sumo pathways.
  PLoS One, 5, e15805.
PDB codes: 3ong 3onh
20142034 M.D.Petroski (2010).
Mechanism-based neddylation inhibitor.
  Chem Biol, 17, 6-8.  
20164921 S.K.Olsen, A.D.Capili, X.Lu, D.S.Tan, and C.D.Lima (2010).
Active site remodelling accompanies thioester bond formation in the SUMO E1.
  Nature, 463, 906-912.
PDB codes: 3kyc 3kyd
19089947 A.M.Burroughs, L.M.Iyer, and L.Aravind (2009).
Natural history of the E1-like superfamily: implication for adenylation, sulfur transfer, and ubiquitin conjugation.
  Proteins, 75, 895-910.  
19352404 B.A.Schulman, and J.W.Harper (2009).
Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways.
  Nat Rev Mol Cell Biol, 10, 319-331.  
19494832 C.A.Regni, R.F.Roush, D.J.Miller, A.Nourse, C.T.Walsh, and B.A.Schulman (2009).
How the MccB bacterial ancestor of ubiquitin E1 initiates biosynthesis of the microcin C7 antibiotic.
  EMBO J, 28, 1953-1964.
PDB codes: 3h5a 3h5n 3h5r 3h9g 3h9j 3h9q
  20948667 C.Riedinger, and J.A.Endicott (2009).
All change: protein conformation and the ubiquitination reaction cascade.
  F1000 Biol Rep, 1, 0.  
19348578 C.T.Jurgenson, T.P.Begley, and S.E.Ealick (2009).
The structural and biochemical foundations of thiamin biosynthesis.
  Annu Rev Biochem, 78, 569-603.  
19942853 E.Siergiejuk, D.C.Scott, B.A.Schulman, K.Hofmann, T.Kurz, and M.Peter (2009).
Cullin neddylation and substrate-adaptors counteract SCF inhibition by the CAND1-like protein Lag2 in Saccharomyces cerevisiae.
  EMBO J, 28, 3845-3856.  
19929613 M.A.Baker, and R.J.Aitken (2009).
Proteomic insights into spermatozoa: critiques, comments and concerns.
  Expert Rev Proteomics, 6, 691-705.  
19423704 Q.S.Fu, C.J.Zhou, H.C.Gao, Y.J.Jiang, Z.R.Zhou, J.Hong, W.M.Yao, A.X.Song, D.H.Lin, and H.Y.Hu (2009).
Structural Basis for Ubiquitin Recognition by a Novel Domain from Human Phospholipase A2-activating Protein.
  J Biol Chem, 284, 19043-19052.
PDB codes: 2k89 2k8a 2k8b 2k8c
19360080 T.A.Soucy, P.G.Smith, M.A.Milhollen, A.J.Berger, J.M.Gavin, S.Adhikari, J.E.Brownell, K.E.Burke, D.P.Cardin, S.Critchley, C.A.Cullis, A.Doucette, J.J.Garnsey, J.L.Gaulin, R.E.Gershman, A.R.Lublinsky, A.McDonald, H.Mizutani, U.Narayanan, E.J.Olhava, S.Peluso, M.Rezaei, M.D.Sintchak, T.Talreja, M.P.Thomas, T.Traore, S.Vyskocil, G.S.Weatherhead, J.Yu, J.Zhang, L.R.Dick, C.F.Claiborne, M.Rolfe, J.B.Bolen, and S.P.Langston (2009).
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.
  Nature, 458, 732-736.  
18560560 E.Pattyn, A.Verhee, I.Uyttendaele, J.Piessevaux, E.Timmerman, K.Gevaert, J.Vandekerckhove, F.Peelman, and J.Tavernier (2008).
HyperISGylation of Old World monkey ISG15 in human cells.
  PLoS ONE, 3, e2427.  
18802447 G.Rabut, and M.Peter (2008).
Function and regulation of protein neddylation. 'Protein modifications: beyond the usual suspects' review series.
  EMBO Rep, 9, 969-976.  
18652489 J.Souphron, M.B.Waddell, A.Paydar, Z.Tokgöz-Gromley, M.F.Roussel, and B.A.Schulman (2008).
Structural dissection of a gating mechanism preventing misactivation of ubiquitin by NEDD8's E1.
  Biochemistry, 47, 8961-8969.
PDB codes: 3dbh 3dbl 3dbr
18353650 M.Groettrup, C.Pelzer, G.Schmidtke, and K.Hofmann (2008).
Activating the ubiquitin family: UBA6 challenges the field.
  Trends Biochem Sci, 33, 230-237.  
18492068 Z.Tang, C.M.Hecker, A.Scheschonka, and H.Betz (2008).
Protein interactions in the sumoylation cascade: lessons from X-ray structures.
  FEBS J, 275, 3003-3015.  
17440617 A.Catic, S.Misaghi, G.A.Korbel, and H.L.Ploegh (2007).
ElaD, a Deubiquitinating protease expressed by E. coli.
  PLoS ONE, 2, e381.  
17919899 A.D.Capili, and C.D.Lima (2007).
Taking it step by step: mechanistic insights from structural studies of ubiquitin/ubiquitin-like protein modification pathways.
  Curr Opin Struct Biol, 17, 726-735.  
17643365 A.L.Haas (2007).
Structural insights into early events in the conjugation of ubiquitin and ubiquitin-like proteins.
  Mol Cell, 27, 174-175.  
17477837 B.T.Dye, and B.A.Schulman (2007).
Structural mechanisms underlying posttranslational modification by ubiquitin-like proteins.
  Annu Rev Biophys Biomol Struct, 36, 131-150.  
17220875 D.T.Huang, H.W.Hunt, M.Zhuang, M.D.Ohi, J.M.Holton, and B.A.Schulman (2007).
Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity.
  Nature, 445, 394-398.
PDB code: 2nvu
17220873 J.F.Trempe, and J.A.Endicott (2007).
Structural biology: pass the protein.
  Nature, 445, 375-376.  
17597759 J.Jin, X.Li, S.P.Gygi, and J.W.Harper (2007).
Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.
  Nature, 447, 1135-1138.  
17217463 S.Goritschnig, Y.Zhang, and X.Li (2007).
The ubiquitin pathway is required for innate immunity in Arabidopsis.
  Plant J, 49, 540-551.  
  20103862 Y.Chen (2007).
The enzymes in ubiquitin-like post-translational modifications.
  Biosci Trends, 1, 16-25.  
16388576 C.Lehmann, T.P.Begley, and S.E.Ealick (2006).
Structure of the Escherichia coli ThiS-ThiF complex, a key component of the sulfur transfer system in thiamin biosynthesis.
  Biochemistry, 45, 11-19.
PDB code: 1zud
16864801 J.Xu, J.Zhang, L.Wang, J.Zhou, H.Huang, J.Wu, Y.Zhong, and Y.Shi (2006).
Solution structure of Urm1 and its implications for the origin of protein modifiers.
  Proc Natl Acad Sci U S A, 103, 11625-11630.
PDB code: 2ax5
16595681 Z.Tokgöz, R.N.Bohnsack, and A.L.Haas (2006).
Pleiotropic effects of ATP.Mg2+ binding in the catalytic cycle of ubiquitin-activating enzyme.
  J Biol Chem, 281, 14729-14737.  
15723079 A.Pichler, P.Knipscheer, E.Oberhofer, W.J.van Dijk, R.Körner, J.V.Olsen, S.Jentsch, F.Melchior, and T.K.Sixma (2005).
SUMO modification of the ubiquitin-conjugating enzyme E2-25K.
  Nat Struct Mol Biol, 12, 264-269.
PDB codes: 2bep 2bf8
15694336 D.T.Huang, A.Paydar, M.Zhuang, M.B.Waddell, J.M.Holton, and B.A.Schulman (2005).
Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1.
  Mol Cell, 17, 341-350.
PDB code: 1y8x
15917233 J.Narasimhan, M.Wang, Z.Fu, J.M.Klein, A.L.Haas, and J.J.Kim (2005).
Crystal structure of the interferon-induced ubiquitin-like protein ISG15.
  J Biol Chem, 280, 27356-27365.
PDB code: 1z2m
15385418 L.A.Rempel, B.R.Francis, K.J.Austin, and T.R.Hansen (2005).
Isolation and sequence of an interferon-tau-inducible, pregnancy- and bovine interferon-stimulated gene product 15 (ISG15)-specific, bovine ubiquitin-activating E1-like (UBE1L) enzyme.
  Biol Reprod, 72, 365-372.  
15660128 L.M.Lois, and C.D.Lima (2005).
Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1.
  EMBO J, 24, 439-451.
PDB codes: 1y8q 1y8r
15775960 L.N.Shen, H.Liu, C.Dong, D.Xirodimas, J.H.Naismith, and R.T.Hay (2005).
Structural basis of NEDD8 ubiquitin discrimination by the deNEDDylating enzyme NEDP1.
  EMBO J, 24, 1341-1351.
PDB codes: 2bkq 2bkr
15774460 R.H.Szczepanowski, R.Filipek, and M.Bochtler (2005).
Crystal structure of a fragment of mouse ubiquitin-activating enzyme.
  J Biol Chem, 280, 22006-22011.
PDB code: 1z7l
15452557 A.P.VanDemark, and C.P.Hill (2004).
Grabbing E2 by the tail.
  Nat Struct Mol Biol, 11, 908-909.  
15131269 C.Zhao, S.L.Beaudenon, M.L.Kelley, M.B.Waddell, W.Yuan, B.A.Schulman, J.M.Huibregtse, and R.M.Krug (2004).
The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein.
  Proc Natl Acad Sci U S A, 101, 7578-7582.  
15361859 D.T.Huang, D.W.Miller, R.Mathew, R.Cassell, J.M.Holton, M.F.Roussel, and B.A.Schulman (2004).
A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8.
  Nat Struct Mol Biol, 11, 927-935.
PDB code: 1tt5
15265004 K.Sugawara, N.N.Suzuki, Y.Fujioka, N.Mizushima, Y.Ohsumi, and F.Inagaki (2004).
The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8.
  Genes Cells, 9, 611-618.
PDB code: 1ugm
15071506 M.Komatsu, T.Chiba, K.Tatsumi, S.Iemura, I.Tanida, N.Okazaki, T.Ueno, E.Kominami, T.Natsume, and K.Tanaka (2004).
A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.
  EMBO J, 23, 1977-1986.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

spacer
spacer