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PDBsum entry 1i1i

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protein metals links
Hydrolase PDB id
1i1i
Jmol
Contents
Protein chain
665 a.a. *
Metals
_ZN ×2
Waters ×172
* Residue conservation analysis
PDB id:
1i1i
Name: Hydrolase
Title: Neurolysin (endopeptidase 24.16) crystal structure
Structure: Neurolysin. Chain: p. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.30Å     R-factor:   0.224     R-free:   0.268
Authors: C.K.Brown,K.Madauss,W.Lian,W.D.Tolbert,M.R.Beck,D.W.Rodgers
Key ref:
C.K.Brown et al. (2001). Structure of neurolysin reveals a deep channel that limits substrate access. Proc Natl Acad Sci U S A, 98, 3127-3132. PubMed id: 11248043 DOI: 10.1073/pnas.051633198
Date:
01-Feb-01     Release date:   28-Feb-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P42676  (NEUL_RAT) -  Neurolysin, mitochondrial
Seq:
Struc:
 
Seq:
Struc:
704 a.a.
665 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.16  - Neurolysin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage in neurotensin: 10-Pro-|-Tyr-11.
      Cofactor: Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     plasma membrane   4 terms 
  Biological process     proteolysis   1 term 
  Biochemical function     hydrolase activity     6 terms  

 

 
DOI no: 10.1073/pnas.051633198 Proc Natl Acad Sci U S A 98:3127-3132 (2001)
PubMed id: 11248043  
 
 
Structure of neurolysin reveals a deep channel that limits substrate access.
C.K.Brown, K.Madauss, W.Lian, M.R.Beck, W.D.Tolbert, D.W.Rodgers.
 
  ABSTRACT  
 
The zinc metallopeptidase neurolysin is shown by x-ray crystallography to have large structural elements erected over the active site region that allow substrate access only through a deep narrow channel. This architecture accounts for specialization of this neuropeptidase to small bioactive peptide substrates without bulky secondary and tertiary structures. In addition, modeling studies indicate that the length of a substrate N-terminal to the site of hydrolysis is restricted to approximately 10 residues by the limited size of the active site cavity. Some structural elements of neurolysin, including a five-stranded beta-sheet and the two active site helices, are conserved with other metallopeptidases. The connecting loop regions of these elements, however, are much extended in neurolysin, and they, together with other open coil elements, line the active site cavity. These potentially flexible elements may account for the ability of the enzyme to cleave a variety of sequences.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Model of substrate peptide binding. A molecular surface representation of neurolysin sectioned to show the large cavity at the bottom of the active-site channel is shown with the 13-residue substrate neurotensin modeled as described in the text. The N terminus of neurotensin is at the top.
Figure 4.
Fig. 4. Sequence selectivity. (A) Aligned sequences for known neurolysin cleavage sites. The sites listed are, top to bottom, from the neuropeptides neurotensin, angiotensin II, bradykinin, dynorphin A (residues 1-8), dynorphin A (residues 1-17), a second site in dynorphin A (residues 1-17), luteninizing hormone-releasing hormone, substance P, and a second site in substance P (8, 35). Residue types are indicated by different colors (blue = basic, brown = aromatic, green = aliphatic, black = proline or glycine, red = polar), and the hydrolysis position is indicated by the vertical line. (B) Details of the active site and nearby disordered loop (light blue; residues 600-612). The zinc cofactor is shown in dark blue and the catalytic water in red. Some side chains from residues in the mobile loop and active site are shown.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21135260 C.Charfi, V.Voisin, L.C.Levros, E.Edouard, and E.Rassart (2011).
Gene profiling of Graffi murine leukemia virus-induced lymphoid leukemias: identification of leukemia markers and Fmn2 as a potential oncogene.
  Blood, 117, 1899-1910.  
18539138 C.E.Isaza, X.Zhong, L.E.Rosas, J.D.White, R.P.Chen, G.F.Liang, S.I.Chan, A.R.Satoskar, and M.K.Chan (2008).
A proposed role for Leishmania major carboxypeptidase in peptide catabolism.
  Biochem Biophys Res Commun, 373, 25-29.  
18393395 E.Yaffe, D.Fishelovitch, H.J.Wolfson, D.Halperin, and R.Nussinov (2008).
MolAxis: efficient and accurate identification of channels in macromolecules.
  Proteins, 73, 72-86.  
  18959747 L.A.Bruce, J.A.Sigman, D.Randall, S.Rodriguez, M.M.Song, Y.Dai, D.E.Elmore, A.Pabon, M.J.Glucksman, and A.J.Wolfson (2008).
Hydrogen bond residue positioning in the 599-611 loop of thimet oligopeptidase is required for substrate selection.
  FEBS J, 275, 5607-5617.  
18499680 T.Kadonosono, M.Kato-Murai, and M.Ueda (2008).
Alteration of substrate specificity of rat neurolysin from matrix metalloproteinase-2/9-type to -3-type specificity by comprehensive mutation.
  Protein Eng Des Sel, 21, 507-513.  
  17277461 A.Kawasaki, H.Nakano, Y.Tsujimoto, H.Matsui, T.Shimizu, T.Nakatsu, H.Kato, and K.Watanabe (2007).
Crystallization and preliminary X-ray crystallographic studies of Pz peptidase A from Geobacillus collagenovorans MO-1.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 142-144.  
17441908 C.Falciani, L.Lozzi, A.Pini, F.Corti, M.Fabbrini, A.Bernini, B.Lelli, N.Niccolai, and L.Bracci (2007).
Molecular basis of branched peptides resistance to enzyme proteolysis.
  Chem Biol Drug Des, 69, 216-221.  
17401561 T.Kadonosono, M.Kato, and M.Ueda (2007).
Substrate specificity of rat brain neurolysin disclosed by molecular display system and putative substrates in rat tissues.
  Appl Microbiol Biotechnol, 75, 1353-1360.  
17404728 T.Kadonosono, M.Kato, and M.Ueda (2007).
Metallopeptidase, neurolysin, as a novel molecular tool for analysis of properties of cancer-producing matrix metalloproteinases-2 and -9.
  Appl Microbiol Biotechnol, 75, 1285-1291.  
17284829 Y.Sugihara, A.Kawasaki, Y.Tsujimoto, H.Matsui, and K.Watanabe (2007).
Potencies of phosphine peptide inhibitors of mammalian thimet oligopeptidase and neurolysin on two bacterial pz peptidases.
  Biosci Biotechnol Biochem, 71, 594-597.  
15937176 R.Miyake, Y.Shigeri, Y.Tatsu, N.Yumoto, M.Umekawa, Y.Tsujimoto, H.Matsui, and K.Watanabe (2005).
Two thimet oligopeptidase-like Pz peptidases produced by a collagen-degrading thermophile, Geobacillus collagenovorans MO-1.
  J Bacteriol, 187, 4140-4148.  
15508121 A.S.Galanis, G.A.Spyroulias, G.Pairas, E.Manessi-Zoupa, and P.Cordopatis (2004).
Solid-phase synthesis and conformational properties of angiotensin converting enzyme catalytic-site peptides: the basis for a structural study on the enzyme-substrate interaction.
  Biopolymers, 76, 512-526.  
14737182 X.I.Ambroggio, D.C.Rees, and R.J.Deshaies (2004).
JAMM: a metalloprotease-like zinc site in the proteasome and signalosome.
  PLoS Biol, 2, E2.
PDB code: 1r5x
12915047 K.Brew (2003).
Structure of human ACE gives new insights into inhibitor binding and design.
  Trends Pharmacol Sci, 24, 391-394.  
14668810 K.R.Acharya, E.D.Sturrock, J.F.Riordan, and M.R.Ehlers (2003).
Ace revisited: a new target for structure-based drug design.
  Nat Rev Drug Discov, 2, 891-902.  
12605218 N.M.Hooper, and A.J.Turner (2003).
An ACE structure.
  Nat Struct Biol, 10, 155-157.  
12540854 R.Natesh, S.L.Schwager, E.D.Sturrock, and K.R.Acharya (2003).
Crystal structure of the human angiotensin-converting enzyme-lisinopril complex.
  Nature, 421, 551-554.
PDB codes: 1o86 1o8a
14566064 S.E.Iismaa, S.Holman, M.A.Wouters, L.Lorand, R.M.Graham, and A.Husain (2003).
Evolutionary specialization of a tryptophan indole group for transition-state stabilization by eukaryotic transglutaminases.
  Proc Natl Acad Sci U S A, 100, 12636-12641.  
14598322 S.I.Kim, V.Grum-Tokars, T.A.Swanson, E.J.Cotter, P.A.Cahill, J.L.Roberts, P.M.Cummins, and M.J.Glucksman (2003).
Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome.
  J Neurosci Res, 74, 456-467.  
11839307 J.W.Arndt, B.Hao, V.Ramakrishnan, T.Cheng, S.I.Chan, and M.K.Chan (2002).
Crystal structure of a novel carboxypeptidase from the hyperthermophilic archaeon Pyrococcus furiosus.
  Structure, 10, 215-224.
PDB codes: 1k9x 1ka2 1ka4
12192079 K.Ray, C.S.Hines, and D.W.Rodgers (2002).
Mapping sequence differences between thimet oligopeptidase and neurolysin implicates key residues in substrate recognition.
  Protein Sci, 11, 2237-2246.  
12199711 V.Oliveira, R.Gatti, V.Rioli, E.S.Ferro, A.Spisni, A.C.Camargo, M.A.Juliano, and L.Juliano (2002).
Temperature and salts effects on the peptidase activities of the recombinant metallooligopeptidases neurolysin and thimet oligopeptidase.
  Eur J Biochem, 269, 4326-4334.  
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.