3G4L

Crystal structure of human phosphodiesterase 4d with roflumilast

PDB DOI: https://doi.org/10.2210/pdb3G4L/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): Yes

Deposited: 2009-02-03 Released: 2010-01-19
Deposition Author(s): Staker, B.L.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.259
R-Value Work: 0.214
R-Value Observed: 0.217

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.

Burgin, A.B., Magnusson, O.T., Singh, J., Witte, P., Staker, B.L., Bjornsson, J.M., Thorsteinsdottir, M., Hrafnsdottir, S., Hagen, T., Kiselyov, A.S., Stewart, L.J., Gurney, M.E.

(2010) Nat Biotechnol 28: 63-70

PubMed: 20037581 Search on PubMed
DOI: https://doi.org/10.1038/nbt.1598
Primary Citation of Related Structures:
3G45, 3G4G, 3G4I, 3G4K, 3G4L, 3G58, 3IAD

PubMed Abstract:
Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.

Organizational Affiliation

deCODE biostructures, Bainbridge Island, Washington, USA. [email protected]

Macromolecule Content

Total Structure Weight: 178.01 kDa
Atom Count: 10,942
Modelled Residue Count: 1,313
Deposited Residue Count: 1,524
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
cAMP-specific 3',5'-cyclic phosphodiesterase 4D	A, B, C, D	381	Homo sapiens	Mutation(s): 2 Gene Names: PDE4D, DPDE3 EC: 3.1.4.17 (PDB Primary Data), 3.1.4.53 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q08499 (Homo sapiens) Explore Q08499 Go to UniProtKB: Q08499
PHAROS: Q08499 GTEx: ENSG00000113448
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q08499
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
ROF Query on ROF Download Ideal Coordinates CCD File SDF format, chain O [auth B] SDF format, chain U [auth C] SDF format, chain Z [auth D] SDF format, chain H [auth A] MOL2 format, chain O [auth B] MOL2 format, chain U [auth C] MOL2 format, chain Z [auth D] MOL2 format, chain H [auth A] mmCIF format, chain O [auth B] mmCIF format, chain U [auth C] mmCIF format, chain Z [auth D] mmCIF format, chain H [auth A]	H [auth A], O [auth B], U [auth C], Z [auth D]	3-(CYCLOPROPYLMETHOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-(DIFLUOROMETHOXY)BENZAMIDE C₁₇ H₁₄ Cl₂ F₂ N₂ O₃ MNDBXUUTURYVHR-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain O [auth B] Focus chain U [auth C] Focus chain Z [auth D] Interactions & Density Focus chain H [auth A] Focus chain O [auth B] Focus chain U [auth C] Focus chain Z [auth D]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain N [auth B] SDF format, chain G [auth A] SDF format, chain T [auth C] SDF format, chain Y [auth D] MOL2 format, chain N [auth B] MOL2 format, chain G [auth A] MOL2 format, chain T [auth C] MOL2 format, chain Y [auth D] mmCIF format, chain N [auth B] mmCIF format, chain G [auth A] mmCIF format, chain T [auth C] mmCIF format, chain Y [auth D]	G [auth A], N [auth B], T [auth C], Y [auth D]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain G [auth A] Focus chain N [auth B] Focus chain T [auth C] Focus chain Y [auth D] Interactions & Density Focus chain G [auth A] Focus chain N [auth B] Focus chain T [auth C] Focus chain Y [auth D]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain L [auth B] SDF format, chain E [auth A] SDF format, chain R [auth C] SDF format, chain W [auth D] MOL2 format, chain L [auth B] MOL2 format, chain E [auth A] MOL2 format, chain R [auth C] MOL2 format, chain W [auth D] mmCIF format, chain L [auth B] mmCIF format, chain E [auth A] mmCIF format, chain R [auth C] mmCIF format, chain W [auth D]	E [auth A], L [auth B], R [auth C], W [auth D]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain L [auth B] Focus chain R [auth C] Focus chain W [auth D] Interactions & Density Focus chain E [auth A] Focus chain L [auth B] Focus chain R [auth C] Focus chain W [auth D]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain AA [auth D] SDF format, chain P [auth B] SDF format, chain BA [auth D] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain Q [auth B] SDF format, chain V [auth C] MOL2 format, chain AA [auth D] MOL2 format, chain P [auth B] MOL2 format, chain BA [auth D] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain V [auth C] mmCIF format, chain AA [auth D] mmCIF format, chain P [auth B] mmCIF format, chain BA [auth D] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain V [auth C]	AA [auth D] BA [auth D] I [auth A] J [auth A] K [auth A] AA [auth D], BA [auth D], I [auth A], J [auth A], K [auth A], P [auth B], Q [auth B], V [auth C]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain AA [auth D] Focus chain BA [auth D] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain P [auth B] Focus chain Q [auth B] Focus chain V [auth C] Interactions & Density Focus chain AA [auth D] Focus chain BA [auth D] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain P [auth B] Focus chain Q [auth B] Focus chain V [auth C]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain M [auth B] SDF format, chain F [auth A] SDF format, chain S [auth C] SDF format, chain X [auth D] MOL2 format, chain M [auth B] MOL2 format, chain F [auth A] MOL2 format, chain S [auth C] MOL2 format, chain X [auth D] mmCIF format, chain M [auth B] mmCIF format, chain F [auth A] mmCIF format, chain S [auth C] mmCIF format, chain X [auth D]	F [auth A], M [auth B], S [auth C], X [auth D]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain M [auth B] Focus chain S [auth C] Focus chain X [auth D] Interactions & Density Focus chain F [auth A] Focus chain M [auth B] Focus chain S [auth C] Focus chain X [auth D]