2CD2

LIGAND INDUCED CONFORMATIONAL CHANGES IN THE CRYSTAL STRUCTURES OF PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE COMPLEXES WITH FOLATE AND NADP+


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+.

Cody, V.Galitsky, N.Rak, D.Luft, J.R.Pangborn, W.Queener, S.F.

(1999) Biochemistry 38: 4303-4312

  • DOI: https://doi.org/10.1021/bi982728m
  • Primary Citation of Related Structures:  
    1CD2, 1E26, 2CD2, 3CD2, 4CD2

  • PubMed Abstract: 

    Structural data from two independent crystal forms (P212121 and P21) of the folate (FA) binary complex and from the ternary complex with the oxidized coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to an average of 2.15 A resolution, show the first evidence of ligand-induced conformational changes in the structure of pcDHFR. These data are also compared with the crystal structure of the ternary complex of methotrexate (MTX) with NADPH and pcDHFR in the monoclinic lattice with data to 2.5 A resolution. Comparison of the data for the FA binary complex of pcDHFR with those for the ternary structures reveals significant differences, with a >7 A movement of the loop region near residue 23 that results in a new "flap-open" position for the binary complex, and a "closed" position in the ternary complexes, similar to that reported for Escherichia coli (ec) DHFR complexes. In the orthorhombic lattice for the binary FA pcDHFR complex, there is also an unwinding of a short helical region near residue 47 that places hydrophobic residues Phe-46 and Phe-49 toward the outer surface, a conformation that is stabilized by intermolecular packing contacts. The pyrophosphate moiety of NADP+ in the ternary folate pcDHFR complexes shows significant differences in conformation compared with that observed in the MTX-NADPH-pcDHFR ternary complex. Additionally, comparison of the conformations among these four pcDHFR structures reveals evidence for subdomain movement that correlates with cofactor binding states. The larger binding site access in the new "flap-open" loop 23 conformation of the binary FA complex is consistent with the rapid release of cofactor from the product complex during catalysis as well as the more rapid release of substrate product from the binary complex as a result of the weaker contacts of the closed loop 23 conformation, compared to ecDHFR.


  • Organizational Affiliation

    Hauptman-Woodward Medical Research Institute, Inc., Buffalo, New York, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DIHYDROFOLATE REDUCTASE206Pneumocystis cariniiMutation(s): 0 
EC: 1.5.1.3
UniProt
Find proteins for P16184 (Pneumocystis carinii)
Explore P16184 
Go to UniProtKB:  P16184
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP16184
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
B [auth A]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
FOL
Query on FOL

Download Ideal Coordinates CCD File 
C [auth A]FOLIC ACID
C19 H19 N7 O6
OVBPIULPVIDEAO-LBPRGKRZSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.305α = 90
b = 43.145β = 94.77
c = 61.147γ = 90
Software Package:
Software NamePurpose
PROLSQrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2000-03-29
    Type: Initial release
  • Version 1.1: 2007-10-16
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-04-04
    Changes: Data collection
  • Version 1.4: 2023-12-27
    Changes: Data collection, Database references, Derived calculations