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PDBsum entry 2c6n

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Hydrolase/hydrolase inhibitor PDB id
2c6n
Jmol
Contents
Protein chain
612 a.a.
Ligands
NAG-NAG ×2
NAG ×3
LPR ×2
GOL ×2
NDG
ACT
Metals
_ZN ×2
_CL ×2
Waters ×19

References listed in PDB file
Key reference
Title Crystal structure of the n domain of human somatic angiotensin i-Converting enzyme provides a structural basis for domain-Specific inhibitor design.
Authors H.R.Corradi, S.L.Schwager, A.T.Nchinda, E.D.Sturrock, K.R.Acharya.
Ref. J Mol Biol, 2006, 357, 964-974. [DOI no: 10.1016/j.jmb.2006.01.048]
PubMed id 16476442
Note In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above were identified by an automated search of PubMed on title and author names, giving a perfect match.
Abstract
Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.
Figure 2.
Figure 2. Sequence alignment of the sACE N domain with tACE and ACE2. Helices are highlighted in yellow and strands in blue. The linker region is shown in pink. Helices are numbered sequentially whether a or 3[10], and 3[10] helices are shown with red letters. Chloride I coordinating residues are boxed in dark blue, chloride II in black, and the zinc binding motif in red.
Figure 3.
Figure 3. (a) Close up of the active site of the N domain (blue/green) and tACE (pink) with the zinc ion in green and the conserved chloride ion in red. Lisinopril is shown in grey/pink for the N domain/tACE, respectively. The lisinopril binding residues are shown in ball and stick. Residues common between the N domain and tACE are in grey (N domain numbering) with differing residues for these two proteins shown in blue/green and pink, respectively. (b) A different orientation of the native N domain active site (blue/green) with RXP407 (grey) approximately positioned using molecular docking. Residues differing between the N domain and tACE (equivalent to the C domain) in the S[2'] and S[2] subsites and the chloride coordinating residues are shown in ball and stick. Residues conserved between the N domain and tACE are shown in grey (N domain numbering), N domain residues are shown in blue/green and tACE residues in pink. The chloride ion is shown in red.
The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 357, 964-974) copyright 2006.
PROCHECK
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