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PDBsum entry 1ot5
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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1ot5

 

 

 

 

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Contents
Protein chains
477 a.a. *
Ligands
ACE-ALA-LYS-BOR ×2
NAG-NAG ×2
NAG ×2
Metals
_CA ×6
Waters ×492
* Residue conservation analysis
PDB id:
1ot5
Name: Hydrolase/hydrolase inhibitor
Title: The 2.4 angstrom crystal structure of kex2 in complex with a peptidyl- boronic acid inhibitor
Structure: Kexin. Chain: a, b. Fragment: residue 123-599. Synonym: kex2 protease, proteinase yscf. Engineered: yes. Ac-ala-lys-boroarg n-acetylated boronic acid peptide inhibitor. Chain: c, d. Engineered: yes
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Gene: kex2 or qds1 or ynl238w or n1122. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Synthetic: yes. Other_details: chemically synthesized n-acetylated-ala-lys-boroarg peptidyl boronic acid inhibitor
Resolution:
2.40Å     R-factor:   0.209     R-free:   0.245
Authors: T.Holyoak,M.A.Wilson,T.D.Fenn,C.A.Kettner,G.A.Petsko,R.S.Fuller, D.Ringe
Key ref:
T.Holyoak et al. (2003). 2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor. Biochemistry, 42, 6709-6718. PubMed id: 12779325 DOI: 10.1021/bi034434t
Date:
21-Mar-03     Release date:   17-Jun-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
P13134  (KEX2_YEAST) -  Kexin from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		 
Seq:
Struc: 		814 a.a.
477 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.21.61  - kexin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage of Lys-Arg-|-Xaa and Arg-Arg-|-Xaa bonds to process Yeast alpha-factor pheromone and killer toxin precursors.

 

 
DOI no: 10.1021/bi034434t Biochemistry 42:6709-6718 (2003)
PubMed id: 12779325  
 
 
2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor.
T.Holyoak, M.A.Wilson, T.D.Fenn, C.A.Kettner, G.A.Petsko, R.S.Fuller, D.Ringe.
 
  ABSTRACT  
 
This paper reports the first structure of a member of the Kex2/furin family of eukaryotic pro-protein processing proteases, which cleave sites consisting of pairs or clusters of basic residues. Reported is the 2.4 A resolution crystal structure of the two-domain protein ssKex2 in complex with an Ac-Ala-Lys-boroArg inhibitor (R = 20.9%, R(free) = 24.5%). The Kex2 proteolytic domain is similar in its global fold to the subtilisin-like superfamily of degradative proteases. Analysis of the complex provides a structural basis for the extreme selectivity of this enzyme family that has evolved from a nonspecific subtilisin-like ancestor. The P-domain of ssKex2 has a novel jelly roll like fold consisting of nine beta strands and may potentially be involved, along with the buried Ca(2+) ion, in creating the highly determined binding site for P(1) arginine.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20038105 G.L.Becker, F.Sielaff, M.E.Than, I.Lindberg, S.Routhier, R.Day, Y.Lu, W.Garten, and T.Steinmetzer (2010).
Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics.
  J Med Chem, 53, 1067-1075.  
19654332 H.Kobayashi, H.Utsunomiya, H.Yamanaka, Y.Sei, N.Katunuma, K.Okamoto, and H.Tsuge (2009).
Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor.
  J Biol Chem, 284, 27655-27663.
PDB code: 3hjr
19300906 M.Rholam, and C.Fahy (2009).
Processing of peptide and hormone precursors at the dibasic cleavage sites.
  Cell Mol Life Sci, 66, 2075-2091.  
19332539 T.Komiyama, J.M.Coppola, M.J.Larsen, M.E.van Dort, B.D.Ross, R.Day, A.Rehemtulla, and R.S.Fuller (2009).
Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules.
  J Biol Chem, 284, 15729-15738.  
18213482 A.N.Tegge, B.R.Southey, J.V.Sweedler, and S.L.Rodriguez-Zas (2008).
Comparative analysis of neuropeptide cleavage sites in human, mouse, rat, and cattle.
  Mamm Genome, 19, 106-120.  
18252740 B.R.Southey, J.V.Sweedler, and S.L.Rodriguez-Zas (2008).
Prediction of neuropeptide cleavage sites in insects.
  Bioinformatics, 24, 815-825.  
18715923 J.Junjhon, M.Lausumpao, S.Supasa, S.Noisakran, A.Songjaeng, P.Saraithong, K.Chaichoun, U.Utaipat, P.Keelapang, A.Kanjanahaluethai, C.Puttikhunt, W.Kasinrerk, P.Malasit, and N.Sittisombut (2008).
Differential modulation of prM cleavage, extracellular particle distribution, and virus infectivity by conserved residues at nonfurin consensus positions of the dengue virus pr-M junction.
  J Virol, 82, 10776-10791.  
18625069 O.Bader, Y.Krauke, and B.Hube (2008).
Processing of predicted substrates of fungal Kex2 proteinases from Candida albicans, C. glabrata, Saccharomyces cerevisiae and Pichia pastoris.
  BMC Microbiol, 8, 116.  
17435765 D.Cunningham, D.E.Danley, K.F.Geoghegan, M.C.Griffor, J.L.Hawkins, T.A.Subashi, A.H.Varghese, M.J.Ammirati, J.S.Culp, L.R.Hoth, M.N.Mansour, K.M.McGrath, A.P.Seddon, S.Shenolikar, K.J.Stutzman-Engwall, L.C.Warren, D.Xia, and X.Qiu (2007).
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.
  Nat Struct Mol Biol, 14, 413-419.
PDB code: 2p4e
17804797 E.N.Hampton, M.W.Knuth, J.Li, J.L.Harris, S.A.Lesley, and G.Spraggon (2007).
The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain.
  Proc Natl Acad Sci U S A, 104, 14604-14609.
PDB code: 2qtw
17426142 J.L.Wheatley, and T.Holyoak (2007).
Differential P1 arginine and lysine recognition in the prototypical proprotein convertase Kex2.
  Proc Natl Acad Sci U S A, 104, 6626-6631.
PDB code: 2id4
17630120 K.Saeki, K.Ozaki, T.Kobayashi, and S.Ito (2007).
Detergent alkaline proteases: enzymatic properties, genes, and crystal structures.
  J Biosci Bioeng, 103, 501-508.  
16934032 H.Tao, Z.Zhang, J.Shi, X.X.Shao, D.Cui, and C.W.Chi (2006).
Template-assisted rational design of peptide inhibitors of furin using the lysine fragment of the mung bean trypsin inhibitor.
  FEBS J, 273, 3907-3914.  
16672242 T.T.Baird, W.D.Wright, and C.S.Craik (2006).
Conversion of trypsin to a functional threonine protease.
  Protein Sci, 15, 1229-1238.  
15858259 M.E.Than, S.Henrich, G.P.Bourenkov, H.D.Bartunik, R.Huber, and W.Bode (2005).
The endoproteinase furin contains two essential Ca2+ ions stabilizing its N-terminus and the unique S1 specificity pocket.
  Acta Crystallogr D Biol Crystallogr, 61, 505-512.  
15925704 M.Fugère, and R.Day (2005).
Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition.
  Trends Pharmacol Sci, 26, 294-301.  
16127065 T.Komiyama, J.A.Swanson, and R.S.Fuller (2005).
Protection from anthrax toxin-mediated killing of macrophages by the combined effects of furin inhibitors and chloroquine.
  Antimicrob Agents Chemother, 49, 3875-3882.  
15159396 L.Rozan, D.J.Krysan, N.C.Rockwell, and R.S.Fuller (2004).
Plasticity of extended subsites facilitates divergent substrate recognition by Kex2 and furin.
  J Biol Chem, 279, 35656-35663.  
15140896 P.Podsiadlo, T.Komiyama, R.S.Fuller, and O.Blum (2004).
Furin inhibition by compounds of copper and zinc.
  J Biol Chem, 279, 36219-36227.  
15342641 T.Nonaka, M.Fujihashi, A.Kita, K.Saeki, S.Ito, K.Horikoshi, and K.Miki (2004).
The crystal structure of an oxidatively stable subtilisin-like alkaline serine protease, KP-43, with a C-terminal beta-barrel domain.
  J Biol Chem, 279, 47344-47351.
PDB codes: 1wmd 1wme 1wmf
14528262 C.Brenner (2003).
Subtleties among subtilases. The structural biology of Kex2 and furin-related prohormone convertases.
  EMBO Rep, 4, 937-938.  
  14617756 R.S.Jackson, J.W.Creemers, I.S.Farooqi, M.L.Raffin-Sanson, A.Varro, G.J.Dockray, J.J.Holst, P.L.Brubaker, P.Corvol, K.S.Polonsky, D.Ostrega, K.L.Becker, X.Bertagna, J.C.Hutton, A.White, M.T.Dattani, K.Hussain, S.J.Middleton, T.M.Nicole, P.J.Milla, K.J.Lindley, and S.O'Rahilly (2003).
Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.
  J Clin Invest, 112, 1550-1560.  
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 code is shown on the right.

 

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