The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme (Journal article)

Tzakos, A. G./ Naqvi, N./ Comporozos, K./ Pierattelli, R./ Theodorou, V./ Husain, A./ Gerothanassis, I. P.

Enzyme-inhibitor recognition is considered one of the most fundamental aspects in the area of drug discovery. However, the molecular mechanism of this recognition process (induced fit or prebinding and adaptive selection among multiple conformers) in several cases remains unexplored. In order to shed light toward this step of the recognition process in the case of human angiotensin I converting enzyme (hACE) and its inhibitor captopril, we have established a novel combinatorial approach exploiting solution NMR, flexible docking calculations, mutagenesis, and enzymatic studies. We provide evidence that an equimolar ratio of the cis and trans states of captopril exists in solution and that the enzyme selects only the trans state of the inhibitor that presents architectural and stereoelectronic complementarity with its substrate binding groove. (c) 2006 Elsevier Ltd. All rights reserved.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας
Keywords: angiotensin-converting enzyme,captopril,isomerization,mutagenesis,nmr,crystal-structure,domain,lisinopril,inhibitors,binding
ISSN: 0960-894X
Link: <Go to ISI>://000240615400020
Publisher: Elsevier
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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