Table 3 Alignment of ACE residues involved in direct interactions with Ac-SDKP compared to the C-domain ACE-AngII and N-domain ACE-RXP407 complexes.

From: Structural basis of Ac-SDKP hydrolysis by Angiotensin-I converting enzyme

Position

N-AcSDKP

Ang II31

RXP407 inhibitor30

N-domain ACE

Corresponding residues in C-ACE

Corresponding residues in N-ACE

C-domain ACE

N-domain ACE

Corresponding residues in C-ACE

S2

  

D336

D358

  

S2

Y369

F391

  

Y369

F391

S2

H388

H410

    

S1

A334

A356

A334

A356

A334

A356

S1

E362

E384

E362

E384

E362

E384

S1

T496

V518

    

S1′

H331

H353

H331

H353

H331

H353

S1′

A332

A354

A332

A354

A332

A354

S1′

T358

V518

    

S1′

H491

H513

H491

H513

H491

H513

S1′

Y501

Y523

Y501

Y523

Y501

Y523

S2′

Q259

Q281

Q259

Q281

Q259

Q281

S2′

K489

K511

K489

K511

K489

K511

S2′

Y498

Y520

Y498

Y520

Y498

Y520

  1. Structural comparison of the two domains of ACE in complex with their preferred substrate (Ac-SDKP for N-domain ACE, and Ang II for C-domain ACE) highlights the common mechanism of peptide recognition. The model of N-domain ACE with its full Ac-SDKP substrate indicates that further direct interactions with N-ACE specific residues are the basis for its domain partiality. Additionally, several potential interactions were distinguished that were not observed in the N-ACE complex structure with RXP407, the most selective N-ACE inhibitor to date.