4KX7

Crystal structure of human aminopeptidase A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structural insights into central hypertension regulation by human aminopeptidase a.

Yang, Y.Liu, C.Lin, Y.L.Li, F.

(2013) J Biol Chem 288: 25638-25645

  • DOI: https://doi.org/10.1074/jbc.M113.494955
  • Primary Citation of Related Structures:  
    4KX7, 4KX8, 4KX9, 4KXA, 4KXB, 4KXC, 4KXD

  • PubMed Abstract: 

    Hypertension is regulated through both the central and systemic renin-angiotensin systems. In the central renin-angiotensin system, zinc-dependent aminopeptidase A (APA) up-regulates blood pressure by specifically cleaving the N-terminal aspartate, but not the adjacent arginine, from angiotensin II, a process facilitated by calcium. Here, we determined the crystal structures of human APA and its complexes with different ligands and identified a calcium-binding site in the S1 pocket of APA. Without calcium, the S1 pocket can bind both acidic and basic residues through formation of salt bridges with the charged side chains. In the presence of calcium, the binding of acidic residues is enhanced as they ligate the cation, whereas the binding of basic residues is no longer favorable due to charge repulsion. Of the peptidomimetic inhibitors of APA, amastatin has higher potency than bestatin by fitting better in the S1 pocket and interacting additionally with the S3' subsite. These results explain the calcium-modulated substrate specificity of APA in central hypertension regulation and can guide the design and development of brain-targeting antihypertensive APA inhibitors.


  • Organizational Affiliation

    From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamyl aminopeptidase888Homo sapiensMutation(s): 2 
Gene Names: ENPEP
EC: 3.4.11.7
UniProt & NIH Common Fund Data Resources
Find proteins for Q07075 (Homo sapiens)
Explore Q07075 
Go to UniProtKB:  Q07075
PHAROS:  Q07075
GTEx:  ENSG00000138792 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07075
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B, C, F
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
D, E
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G47362BJ
GlyCosmos:  G47362BJ
GlyGen:  G47362BJ
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 
  • Space Group: P 64 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 142.34α = 90
b = 142.34β = 90
c = 237.446γ = 120
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-07-31
    Type: Initial release
  • Version 1.1: 2013-09-04
    Changes: Database references
  • Version 1.2: 2013-10-09
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2022-12-21
    Changes: Database references, Structure summary