4RE5

Acylaminoacyl peptidase complexed with a chloromethylketone inhibitor

Summary for 4RE5

• Entry DOI: 10.2210/pdb4re5/pdb
• Related: 4RE6
• Related PRD ID: PRD_001053
• Descriptor: Acylamino-acid-releasing enzyme, N-[(benzyloxy)carbonyl]glycyl-N-[(2S,3R)-4-chloro-3-hydroxy-1-phenylbutan-2-yl]glycinamide, ACETATE ION, ... (6 entities in total)
• Functional Keywords: beta-propeller, alpha-beta-hydrolase fold, chloromethyl-ketone inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Aeropyrum pernix
• Total number of polymer chains: 2
• Total formula weight: 127561.94

Authors

Menyhard, D.K.,Orgovan, Z.,Szeltner, Z.,Szamosi, I.,Harmat, V. (deposition date: 2014-09-22, release date: 2015-01-28, Last modification date: 2024-11-06)

Primary citation

Menyhard, D.K.,Orgovan, Z.,Szeltner, Z.,Szamosi, I.,Harmat, V.
Catalytically distinct states captured in a crystal lattice: the substrate-bound and scavenger states of acylaminoacyl peptidase and their implications for functionality.
Acta Crystallogr.,Sect.D, 71:461-472, 2015

PubMed Abstract: Acylaminoacyl peptidase (AAP) is an oligopeptidase that only cleaves short peptides or protein segments. In the case of AAP from Aeropyrum pernix (ApAAP), previous studies have led to a model in which the clamshell-like opening and closing of the enzyme provides the means of substrate-size selection. The closed form of the enzyme is catalytically active, while opening deactivates the catalytic triad. The crystallographic results presented here show that the open form of ApAAP is indeed functionally disabled. The obtained crystal structures also reveal that the closed form is penetrable to small ligands: inhibitor added to the pre-formed crystal was able to reach the active site of the rigidified protein, which is only possible through the narrow channel of the propeller domain. Molecular-dynamics simulations investigating the structure of the complexes formed with longer peptide substrates showed that their binding within the large crevice of the closed form of ApAAP leaves the enzyme structure unperturbed; however, their accessing the binding site seems more probable when assisted by opening of the enzyme. Thus, the open form of ApAAP corresponds to a scavenger of possible substrates, the actual cleavage of which only takes place if the enzyme is able to re-close.

PubMed: 25760596
DOI: 10.1107/S1399004714026819

Experimental method

X-RAY DIFFRACTION (1.9 Å)