3SHZ | pdb_00003shz

Crystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors

PDB DOI: https://doi.org/10.2210/pdb3SHZ/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2011-06-17 Released: 2011-08-24
Deposition Author(s): Chen, T.T., Chen, T., Xu, Y.C.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.45 Å
R-Value Free:
0.245 (Depositor), 0.240 (DCC)
R-Value Work:
0.201 (Depositor), 0.200 (DCC)
R-Value Observed:
0.203 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Utilization of Halogen Bond in Lead Optimization: A Case Study of Rational Design of Potent Phosphodiesterase Type 5 (PDE5) Inhibitors.

Xu, Z., Liu, Z., Chen, T., Chen, T.T., Wang, Z., Tian, G., Shi, J., Wang, X., Lu, Y., Yan, X., Wang, G., Jiang, H., Chen, K., Wang, S., Xu, Y., Shen, J., Zhu, W.

(2011) J Med Chem 54: 5607-5611

PubMed: 21714539 Search on PubMed
DOI: https://doi.org/10.1021/jm200644r
Primary Citation of Related Structures:
3SHY, 3SHZ, 3SIE

PubMed Abstract:
For proof-of-concept of halogen bonding in drug design, a series of halogenated compounds were designed based on a lead structure as new inhibitors of phosphodiesterase type 5. Bioassay results revealed a good correlation between the measured bioactivity and the calculated halogen bond energy. Our X-ray crystal structures verified the existence of the predicted halogen bonds, demonstrating that the halogen bond is an applicable tool in drug design and should be routinely considered in lead optimization.

Organizational Affiliation

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Macromolecule Content

Total Structure Weight: 40.73 kDa
Atom Count: 2,350
Modelled Residue Count: 297
Deposited Residue Count: 347
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
cGMP-specific 3',5'-cyclic phosphodiesterase	A	347	Homo sapiens	Mutation(s): 0 Gene Names: PDE5, PDE5A EC: 3.1.4.35
UniProt & NIH Common Fund Data Resources
Find proteins for O76074 (Homo sapiens) Explore O76074 Go to UniProtKB: O76074
PHAROS: O76074 GTEx: ENSG00000138735
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O76074
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
5CO Query on 5CO Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	5-chloro-6-ethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]-2-propoxyphenyl}pyrimidin-4(3H)-one C₂₀ H₂₇ Cl N₄ O₄ S HVJOKVUJWQTZFF-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain D [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain D [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	D [auth A], E [auth A], F [auth A], G [auth A], H [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
5CO	BindingDB: 3SHZ	Kd: 770 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.45 Å
R-Value Free: 0.245 (Depositor), 0.240 (DCC)
R-Value Work: 0.201 (Depositor), 0.200 (DCC)
R-Value Observed: 0.203 (Depositor)

Space Group: P 3₁ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 74.687	α = 90
b = 74.687	β = 90
c = 131.728	γ = 120

Software Package:

Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
PHENIX	refinement
PDB_EXTRACT	data extraction
ADSC	data collection
HKL-2000	data reduction
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-08-24

Deposition Author(s):

Chen, T.T.

Chen, T.

Xu, Y.C.

Revision History (Full details and data files)

Version 1.0: 2011-08-24
Type: Initial release
Version 1.1: 2017-11-08
Changes: Refinement description
Version 1.2: 2024-03-20
Changes: Data collection, Database references, Derived calculations