2001
DOI: 10.1073/pnas.051633198
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Structure of neurolysin reveals a deep channel that limits substrate access

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 t… Show more

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Cited by 127 publications
(176 citation statements)
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References 47 publications
(47 reference statements)
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“…Unlike similar investigations with other mammalian zinc metallopeptidases that address the functionality of one or two residues, we performed a comprehensive examination of seven residues postulated to function in the zinc coordination of EcDCP active site. The catalytic cores of neurolysin, EcDCP, and EP24.15 have revealed a binding site for divalent metal ions with two histidines and one glutamate as ligands (Cummins et al 1999;Brown et al 2001;Comellas-Bigler et al 2005). Our experimental data support this hypothesis and thus provide a vital key towards understanding the catalytic mechanism to the family M3 enzymes.…”
Section: Discussionsupporting
confidence: 72%
See 1 more Smart Citation
“…Unlike similar investigations with other mammalian zinc metallopeptidases that address the functionality of one or two residues, we performed a comprehensive examination of seven residues postulated to function in the zinc coordination of EcDCP active site. The catalytic cores of neurolysin, EcDCP, and EP24.15 have revealed a binding site for divalent metal ions with two histidines and one glutamate as ligands (Cummins et al 1999;Brown et al 2001;Comellas-Bigler et al 2005). Our experimental data support this hypothesis and thus provide a vital key towards understanding the catalytic mechanism to the family M3 enzymes.…”
Section: Discussionsupporting
confidence: 72%
“…The three-dimensional structures of five related zinc metallopeptidases, thermolysin (Holmes & Matthews 1982), elastase (Thayer et al 1991), neutral protease (Stark et al 1992), neurolysin (Brown et al 2001) and EcDCP (Comellas-Bigler et al 2005) have been previously solved by X-ray crystallographic analyses. In the active-site centers of these enzymes, a zinc ion is coordinated to the side-chains of three amino acid residues and a water molecule (Matthews et al 1972;Matthews 1988;Vallee & Auld 1990a).…”
Section: Introductionmentioning
confidence: 99%
“…The OOP homolog E. coli dipeptidyl carboxypeptidase has been crystallized in a closed conformation similar to the OOP structure presented here (rmsd 1.7 Å) (37). In contrast to the closed conformation of OOP, the mammalian homologs neurolysin and thimet oligopeptidase (TOP) were crystallized in open conformations (38,39). The catalytic site of OOP is buried within a long internal cavity (Fig.…”
Section: Structure Of Oop With Bound Peptide Reveals the Molecular Bamentioning
confidence: 99%
“…7b and c) chlorine (Ehlers and Kirsch, 1988). Similarly prominent deep clefts have been observed from neurolysin (Brown et al, 2001) and a carboxypeptidase from the hyperthermophilic archaeon Pyrococcus furiosus (Arndt et al, 2002). Both enzymes are functionally homologous to ACE and belong to the metalloprotease (zincin) superfamily (Sturrock et al, 2004).…”
Section: N-terminal Sequence Of the N-and C-domainsmentioning
confidence: 84%