Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.

@article{Watermeyer2010CharacterizationOD,
  title={Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.},
  author={Jean M. Watermeyer and Wendy L. Kr{\"o}ger and Hester G. O’Neill and Bryan Trevor Sewell and Edward D. Sturrock},
  journal={The Biochemical journal},
  year={2010},
  volume={428 1},
  pages={
          67-74
        }
}
Human ACE (angiotensin-converting enzyme) (EC 3.4.15.1) is an important drug target because of its role in the regulation of blood pressure via the renin-angiotensin-aldosterone system. Somatic ACE comprises two homologous domains, the differing substrate preferences of which present a new avenue for domain-selective inhibitor design. We have co-crystallized lisW-S, a C-domain-selective derivative of the drug lisinopril, with human testis ACE and determined a structure using X-ray… 
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References

SHOWING 1-10 OF 54 REFERENCES

The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380.

The characterization of the extended active site and the binding of a potent C-domain-selective inhibitor provide the first structural data for the design of truly domain-specific pharmacophores.

The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors.

Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.

Crystal structure of the human angiotensin-converting enzyme–lisinopril complex

Three-dimensional analysis of the three-dimensional structure of human testicular ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxy-zinc metallopeptidases with no detectable sequence similarity to ACE.

The two homologous domains of human angiotensin I-converting enzyme are both catalytically active.

Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme.

High-resolution crystal structures of testis ACE in complex with the first successfully designed ACE inhibitor captopril and enalaprilat, the Phe-Ala-Pro analogue are reported and the molecular details provided will be used to improve the binding and/or the design of new, more potent domain-specific inhibitors of ACE that could serve as new generation antihypertensive drugs.

Investigating the domain specificity of phosphinic inhibitors RXPA380 and RXP407 in angiotensin-converting enzyme.

Understanding is Advance regarding the molecular basis for the remarkable ACE domain selectivity exhibited by these inhibitors is advanced.

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

It is shown that the C-domain of ACE is the predominant site of angiotensin I cleavage in vivo, and although mice lacking C- domain activity have normal physiology under laboratory conditions, they respond less well to the stress of dehydration.

Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme.

Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling

D determinations indicated that the introduction of a bulky aromatic tryptophan at the P2′ position of keto-ACE significantly increased selectivity for the C-domain, while an aliphatic P2 Boc group conferred N-domain selectivity.
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