6I6C

SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 2

PDB DOI: https://doi.org/10.2210/pdb6I6C/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2018-11-15 Released: 2019-07-10
Deposition Author(s): Alen, J., Schade, M., Wagener, M., Blaesse, M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.72 ?
R-Value Free: 0.206
R-Value Work: 0.149
R-Value Observed: 0.152

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.

Alen, J., Schade, M., Wagener, M., Christian, F., Nordhoff, S., Merla, B., Dunkern, T.R., Bahrenberg, G., Ratcliffe, P.

(2019) J Med Chem 62: 6391-6397

PubMed: 31244106 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.9b00218
Primary Citation of Related Structures:
6I6C, 6I6F, 6I6P, 6I6T, 6I6V, 6I79

PubMed Abstract:
Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used ¹⁹F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency.

Organizational Affiliation

Grünenthal GmbH , Zieglerstra?e 6 , 52078 Aachen , Germany.

Macromolecule Content

Total Structure Weight: 62.5 kDa
Atom Count: 4,450
Modelled Residue Count: 523
Deposited Residue Count: 552
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Sepiapterin reductase	A, B	276	Homo sapiens	Mutation(s): 0 Gene Names: SPR EC: 1.1.1.153
UniProt & NIH Common Fund Data Resources
Find proteins for P35270 (Homo sapiens) Explore P35270 Go to UniProtKB: P35270
PHAROS: P35270 GTEx: ENSG00000116096
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P35270
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAP Query on NAP Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain H [auth B] mmCIF format, chain C [auth A] mmCIF format, chain H [auth B]	C [auth A], H [auth B]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain C [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain H [auth B]
H4H Query on H4H Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain I [auth B] MOL2 format, chain D [auth A] MOL2 format, chain I [auth B] mmCIF format, chain D [auth A] mmCIF format, chain I [auth B]	D [auth A], I [auth B]	(1~{R},2~{S},4~{S})-~{N}-(3-chloranyl-4-cyano-phenyl)sulfonylbicyclo[2.2.1]heptane-2-carboxamide C₁₅ H₁₅ Cl N₂ O₃ S RHQQLCMXOXXSOP-CWSCBRNRSA-N		Interactions Focus chain D [auth A] Focus chain I [auth B] Interactions & Density Focus chain D [auth A] Focus chain I [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] MOL2 format, chain G [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] mmCIF format, chain G [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B]	E [auth A] F [auth A] G [auth A] J [auth B] K [auth B] E [auth A], F [auth A], G [auth A], J [auth B], K [auth B], L [auth B], M [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.72 ?
R-Value Free: 0.206
R-Value Work: 0.149
R-Value Observed: 0.152
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 113.913	α = 90
b = 77.321	β = 90
c = 59.214	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
XSCALE	data scaling
REFMAC	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-07-10

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2019-07-10
Type: Initial release
Version 1.1: 2019-07-24
Changes: Data collection, Database references
Version 1.2: 2024-05-15
Changes: Advisory, Data collection, Database references

Prepare Data

Validate Data

Deposit Data

Help and Resources

6I6C

SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 2

Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

Expand

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)