7MWV

Structure of the E. coli PutA proline dehydrogenase domain (residues 86-630) complexed with cyclopropanecarboxylic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

Structure-affinity relationships of reversible proline analog inhibitors targeting proline dehydrogenase.

Bogner, A.N.Tanner, J.J.

(2022) Org Biomol Chem 20: 895-905

  • DOI: https://doi.org/10.1039/d1ob02328d
  • Primary Citation of Related Structures:  
    7MWT, 7MWU, 7MWV, 7SQN

  • PubMed Abstract: 

    Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the FAD-dependent oxidation of L-proline to Δ 1 -pyrroline-5-carboxylate. PRODH plays a central role in the metabolic rewiring of cancer cells, which has motivated the discovery of inhibitors. Here, we studied the inhibition of PRODH by 18 proline-like compounds to understand the structural and chemical features responsible for the affinity of the best-known inhibitor, S -(-)-tetrahydro-2-furoic acid (1). The compounds were screened, and then six were selected for more thorough kinetic analysis: cyclobutane-1,1-dicarboxylic acid (2), cyclobutanecarboxylic acid (3), cyclopropanecarboxylic acid (4), cyclopentanecarboxylic acid (16), 2-oxobutyric acid (17), and (2 S )-oxetane-2-carboxylic acid (18). These compounds are competitive inhibitors with inhibition constants in the range of 1.4-6 mM, compared to 0.3 mM for 1. Crystal structures of PRODH complexed with 2, 3, 4, and 18 were determined. All four inhibitors bind in the proline substrate site, but the orientations of their rings differ from that of 1. The binding of 3 and 18 is accompanied by compression of the active site to enable nonpolar contacts with Leu513. Compound 2 is unique in that the additional carboxylate displaces a structurally conserved water molecule from the active site. Compound 18 also destabilizes the conserved water, but by an unexpected non-steric mechanism. The results are interpreted using a chemical double mutant thermodynamic cycle. This analysis revealed unanticipated synergism between ring size and hydrogen bonding to the conserved water. These structure-affinity relationships provide new information relevant to the development of new inhibitor design strategies targeting PRODH.


  • Organizational Affiliation

    Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA. [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bifunctional protein PutA551Escherichia coliMutation(s): 0 
Gene Names: putASAMEA3472047_03659
EC: 1.5.5.2 (PDB Primary Data), 1.2.1.88 (PDB Primary Data)
UniProt
Find proteins for P09546 (Escherichia coli (strain K12))
Explore P09546 
Go to UniProtKB:  P09546
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09546
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.991α = 90
b = 141.738β = 90
c = 146.299γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States1R01GM132640

Revision History  (Full details and data files)

  • Version 1.0: 2022-01-19
    Type: Initial release
  • Version 1.1: 2022-02-02
    Changes: Database references
  • Version 1.2: 2022-02-09
    Changes: Database references
  • Version 1.3: 2023-10-18
    Changes: Data collection, Refinement description