2NSM

Crystal structure of the human carboxypeptidase N (Kininase I) catalytic domain

Summary for 2NSM

• Entry DOI: 10.2210/pdb2nsm/pdb
• Descriptor: Carboxypeptidase N catalytic chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (4 entities in total)
• Functional Keywords: caroxypeptidase, zinc peptidase, transthyretin-like domain, hormone processing, peptide modification, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space: P15169
• Total number of polymer chains: 1
• Total formula weight: 51232.31

Authors

Keil, C.,Maskos, K.,Than, M.,Hoopes, J.T.,Huber, R.,Tan, F.,Deddish, P.A.,Erdoes, E.G.,Skidgel, R.A.,Bode, W. (deposition date: 2006-11-05, release date: 2007-04-24, Last modification date: 2024-11-20)

Primary citation

Keil, C.,Maskos, K.,Than, M.,Hoopes, J.T.,Huber, R.,Tan, F.,Deddish, P.A.,Erdoes, E.G.,Skidgel, R.A.,Bode, W.
Crystal structure of the human carboxypeptidase N (kininase I) catalytic domain
J.Mol.Biol., 366:504-516, 2007

PubMed Abstract: Human carboxypeptidase N (CPN), a member of the CPN/E subfamily of "regulatory" metallo-carboxypeptidases, is an extracellular glycoprotein synthesized in the liver and secreted into the blood, where it controls the activity of vasoactive peptide hormones, growth factors and cytokines by specifically removing C-terminal basic residues. Normally, CPN circulates in blood plasma as a hetero-tetramer consisting of two 83 kDa (CPN2) domains each flanked by a 48 to 55 kDa catalytic (CPN1) domain. We have prepared and crystallized the recombinant C-terminally truncated catalytic domain of human CPN1, and have determined and refined its 2.1 A crystal structure. The structural analysis reveals that CPN1 has a pear-like shape, consisting of a 319 residue N-terminal catalytic domain and an abutting, cylindrically shaped 79 residue C-terminal beta-sandwich transthyretin (TT) domain, more resembling CPD-2 than CPM. Like these other CPN/E members, two surface loops surrounding the active-site groove restrict access to the catalytic center, offering an explanation for why some larger protein carboxypeptidase inhibitors do not inhibit CPN. Modeling of the Pro-Phe-Arg C-terminal end of the natural substrate bradykinin into the active site shows that the S1' pocket of CPN1 might better accommodate P1'-Lys than Arg residues, in agreement with CPN's preference for cleaving off C-terminal Lys residues. Three Thr residues at the distal TT edge of CPN1 are O-linked to N-acetyl glucosamine sugars; equivalent sites in the membrane-anchored CPM are occupied by basic residues probably involved in membrane interaction. In tetrameric CPN, each CPN1 subunit might interact with the central leucine-rich repeat tandem of the cognate CPN2 subunit via a unique hydrophobic surface patch wrapping around the catalytic domain-TT interface, exposing the two active centers.

PubMed: 17157876
DOI: 10.1016/j.jmb.2006.11.025

Experimental method

X-RAY DIFFRACTION (2.1 Å)