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Structure of testis ACE glycosylation mutants and evidence for conserved domain movement.

Watermeyer JM, Sewell BT, Schwager SL, Natesh R, Corradi HR, Acharya KR, Sturrock ED
Biochemistry 45 12654-63 (2006)
Cited: 33 times
EuropePMC logo PMID: 17042482

Abstract

Human angiotensin-converting enzyme is an important drug target for which little structural information has been available until recent years. The slow progress in obtaining a crystal structure was due to the problem of surface glycosylation, a difficulty that has thus far been overcome by the use of a glucosidase-1 inhibitor in the tissue culture medium. However, the prohibitive cost of these inhibitors and incomplete glucosidase inhibition makes alternative routes to minimizing the N-glycan heterogeneity desirable. Here, glycosylation in the testis isoform (tACE) has been reduced by Asn-Gln point mutations at N-glycosylation sites, and the crystal structures of mutants having two and four intact sites have been solved to 2.0 A and 2.8 A, respectively. Both mutants show close structural identity with the wild-type. A hinge mechanism is proposed for substrate entry into the active cleft, based on homology to human ACE2 at the levels of sequence and flexibility. This is supported by normal-mode analysis that reveals intrinsic flexibility about the active site of tACE. Subdomain II, containing bound chloride and zinc ions, is found to have greater stability than subdomain I in the structures of three ACE homologues. Crystallizable glycosylation mutants open up new possibilities for cocrystallization studies to aid the design of novel ACE inhibitors.

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  1. Molecular docking screens using comparative models of proteins. Fan H, Irwin JJ, Webb BM, Klebe G, Shoichet BK, Sali A. J Chem Inf Model 49 2512-2527 (2009)
  2. Structure of testis ACE glycosylation mutants and evidence for conserved domain movement. Watermeyer JM, Sewell BT, Schwager SL, Natesh R, Corradi HR, Acharya KR, Sturrock ED. Biochemistry 45 12654-12663 (2006)
  3. Cross-strand disulfides in the hydrogen bonding site of antiparallel β-sheet (aCSDhs): Forbidden disulfides that are highly strained, easily broken. Haworth NL, Wouters MJ, Hunter MO, Ma L, Wouters MA. Protein Sci 28 239-256 (2019)


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  1. Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function. Erdös EG, Tan F, Skidgel RA. Hypertension 55 214-220 (2010)
  2. Targeting the renin-angiotensin-aldosterone system in fibrosis. AlQudah M, AlQudah M, Hale TM, Czubryt MP. Matrix Biol 91-92 92-108 (2020)
  3. ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. Lubbe L, Cozier GE, Oosthuizen D, Acharya KR, Sturrock ED. Clin Sci (Lond) 134 2851-2871 (2020)
  4. Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence. Masuyer G, Yates CJ, Sturrock ED, Acharya KR. Biol Chem 395 1135-1149 (2014)
  5. Severe Acute Respiratory Syndrome Coronavirus 2 and Male Reproduction: Relationship, Explanations, and Clinical Remedies. Xu J, He L, Zhang Y, Hu Z, Su Y, Fang Y, Peng M, Fan Z, Liu C, Zhao K, Zhang H. Front Physiol 12 651408 (2021)
  6. Interacting cogs in the machinery of the renin angiotensin system. Lubbe L, Sturrock ED. Biophys Rev 583-589 (2019)

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  1. The N domain of human angiotensin-I-converting enzyme: the role of N-glycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407. Anthony CS, Corradi HR, Schwager SL, Redelinghuys P, Georgiadis D, Dive V, Acharya KR, Sturrock ED. J Biol Chem 285 35685-35693 (2010)
  2. Can ACE2 Receptor Polymorphism Predict Species Susceptibility to SARS-CoV-2? Devaux CA, Pinault L, Osman IO, Raoult D. Front Public Health 8 608765 (2020)
  3. Inhibition mechanism and model of an angiotensin I-converting enzyme (ACE)-inhibitory hexapeptide from yeast (Saccharomyces cerevisiae). Ni H, Li L, Liu G, Hu SQ. PLoS One 7 e37077 (2012)
  4. Molecular and thermodynamic mechanisms of the chloride-dependent human angiotensin-I-converting enzyme (ACE). Yates CJ, Masuyer G, Schwager SL, Akif M, Sturrock ED, Acharya KR. J Biol Chem 289 1798-1814 (2014)
  5. Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking to the cell surface resulting in selective denaturation of the C-domain. Danilov SM, Kalinin S, Chen Z, Vinokour EI, Nesterovitch AB, Schwartz DE, Gribouval O, Gubler MC, Minshall RD. PLoS One 5 e10438 (2010)
  6. Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. Watermeyer JM, Kröger WL, O'Neill HG, Sewell BT, Sturrock ED. Biochem J 428 67-74 (2010)
  7. Epitope mapping of mAbs to denatured human testicular ACE (CD143). Balyasnikova IV, Metzger R, Franke FE, Conrad N, Towbin H, Schwartz DE, Sturrock ED, Danilov SM. Tissue Antigens 72 354-368 (2008)
  8. Inhibitor and substrate binding by angiotensin-converting enzyme: quantum mechanical/molecular mechanical molecular dynamics studies. Wang X, Wu S, Xu D, Xie D, Guo H. J Chem Inf Model 51 1074-1082 (2011)
  9. Porcine pulmonary angiotensin I-converting enzyme--biochemical characterization and spatial arrangement of the N- and C-domains by three-dimensional electron microscopic reconstruction. Chen HL, Lünsdorf H, Hecht HJ, Tsai H. Micron 41 674-685 (2010)
  10. Functional regulation of sugar assimilation by N-glycan-specific interaction of pancreatic α-amylase with glycoproteins of duodenal brush border membrane. Asanuma-Date K, Hirano Y, Le N, Sano K, Kawasaki N, Hashii N, Hiruta Y, Nakayama K, Umemura M, Ishikawa K, Sakagami H, Ogawa H. J Biol Chem 287 23104-23118 (2012)
  11. Insight into the interactive residues between two domains of human somatic Angiotensin-converting enzyme and Angiotensin II by MM-PBSA calculation and steered molecular dynamics simulation. Guan SS, Han WW, Zhang H, Wang S, Shan YM. J Biomol Struct Dyn 34 15-28 (2016)
  12. The influence of angiotensin converting enzyme mutations on the kinetics and dynamics of N-domain selective inhibition. Lubbe L, Sewell BT, Sturrock ED. FEBS J 283 3941-3961 (2016)
  13. The role of glycosylation and domain interactions in the thermal stability of human angiotensin-converting enzyme. O'Neill HG, Redelinghuys P, Schwager SL, Sturrock ED. Biol Chem 389 1153-1161 (2008)
  14. Angiotensin-converting enzyme open for business: structural insights into the subdomain dynamics. Cozier GE, Lubbe L, Sturrock ED, Acharya KR. FEBS J 288 2238-2256 (2021)
  15. Thermodynamic determination of the binding constants of angiotensin-converting enzyme inhibitors by a displacement method. Andújar-Sánchez M, Jara-Pérez V, Cámara-Artigas A. FEBS Lett 581 3449-3454 (2007)
  16. ACE-domain selectivity extends beyond direct interacting residues at the active site. Cozier GE, Lubbe L, Sturrock ED, Acharya KR. Biochem J 477 1241-1259 (2020)
  17. Spontaneous Hinge-Bending Motions of Angiotensin I Converting Enzyme: Role in Activation and Inhibition. Vy TT, Heo SY, Jung WK, Yi M. Molecules 25 E1288 (2020)
  18. Comparison of the Internal Dynamics of Metalloproteases Provides New Insights on Their Function and Evolution. Carvalho HF, Roque AC, Iranzo O, Branco RJ. PLoS One 10 e0138118 (2015)
  19. Study of a lipophilic captopril analogue binding to angiotensin I converting enzyme. Dalkas GA, Marchand D, Galleyrand JC, Martinez J, Spyroulias GA, Cordopatis P, Cavelier F. J Pept Sci 16 91-97 (2010)
  20. Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerization. Lubbe L, Sewell BT, Woodward JD, Sturrock ED. EMBO J 41 e110550 (2022)
  21. Interaction of hemorphins with ACE homologs. Jobe A, Antony P, Altabbal S, Al Dhaheri Y, Vijayan R. Sci Rep 13 3743 (2023)
  22. Urinary ACE Phenotyping as a Research and Diagnostic Tool: Identification of Sex-Dependent ACE Immunoreactivity. Kozuch AJ, Petukhov PA, Fagyas M, Popova IA, Lindeblad MO, Bobkov AP, Kamalov AA, Toth A, Dudek SM, Danilov SM. Biomedicines 11 953 (2023)


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