3NZD

Structural Analysis of Pneumocystis carinii and Human DHFR Complexes with NADPH and a Series of Five 5-(omega-carboxy(alkyloxy(pyrido[2,3-d]pyrimidine Derivatives


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.167 

Starting Model: experimental
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Literature

Structural analysis of Pneumocystis carinii and human DHFR complexes with NADPH and a series of five potent 6-[5'-([omega]-carboxyalkoxy)benzyl]pyrido[2,3-d]pyrimidine derivatives

Cody, V.Pace, J.

(2011) Acta Crystallogr D Biol Crystallogr 67: 1-7

  • DOI: https://doi.org/10.1107/S0907444910041004
  • Primary Citation of Related Structures:  
    3NZ6, 3NZ9, 3NZA, 3NZB, 3NZC, 3NZD

  • PubMed Abstract: 

    Structural data are reported for five antifolates, namely 2,4-diamino-6-[5'-(5-carboxypentyloxy)-2'-methoxybenzyl]-5-methylpyrido[2,3-d]pyrimidine, (1), and the 5'-[3-(ethoxycarbonyl)propoxy]-, (2), 5'-[3-(ethoxycarbonyl)butoxy]-, (3), 5'-[3-(ethoxycarbonyl)pentyloxy]-, (4), and 5'-benzyloxy-, (5), derivatives, which are potent and selective for Pneumocystis carinii dihydrofolate reductase (pcDHFR). Crystal structures are reported for their ternary complexes with NADPH and pcDHFR refined to between 1.4 and 2.0 Å resolution and for that of 3 with human DHFR (hDHFR) to 1.8 Å resolution. These data reveal that the carboxylate of the ω-carboxyalkoxy side chain of 1, the most potent inhibitor in this series, forms ionic interactions with the conserved Arg75 in the substrate-binding pocket of pcDHFR, whereas the less potent ethyl esters of 2-4 bind with variable side-chain conformations. The benzyloxy side chain of 5 makes no contact with Arg75 and is the least active inhibitor in this series. These structural results suggest that the weaker binding of this series compared with that of their pyrimidine homologs in part arises from the flexibility observed in their side-chain conformations, which do not optimize intermolecular contact to Arg75. Structural data for the binding of 3 to both hDHFR and pcDHFR reveals that the inhibitor binds in two different conformations, one similar to each of the two conformations observed for the parent pyrido[2,3-d]pyrimidine, piritrexim (PTX), bound to hDHFR. The structure of the pcDHFR complex of 4 reveals disorder in the side-chain orientation; one orientation has the ω-carboxyalkoxy side chain positioned in the folate-binding pocket similar to the others in this series, while the second orientation occupies a new site near the nicotinamide ring of NADPH. This alternate binding site has not been observed in other DHFR structures. Structural data for the pcDHFR complex of 5 show that its benzyl side chain forms intermolecular van der Waals interactions with Phe69 in the binding pocket that could account for its enhanced binding selectivity compared with the other analogs in this series.


  • Organizational Affiliation

    Structural Biology Department, Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductase186Homo sapiensMutation(s): 0 
Gene Names: DHFRDHFRP1
EC: 1.5.1.3
UniProt & NIH Common Fund Data Resources
Find proteins for P00374 (Homo sapiens)
Explore P00374 
Go to UniProtKB:  P00374
PHAROS:  P00374
GTEx:  ENSG00000228716 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00374
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
C [auth A]NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
D2Q
Query on D2Q

Download Ideal Coordinates CCD File 
B [auth A]ethyl 5-{2-[(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]-4-methoxyphenoxy}pentanoate
C23 H29 N5 O4
BHQORMWWDFDSIW-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.167 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.622α = 90
b = 84.622β = 90
c = 77.597γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-12-29 
  • Deposition Author(s): Cody, V.

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-29
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description