5V48

Soluble rabbit neprilysin in complex with thiorphan

PDB DOI: https://doi.org/10.2210/pdb5V48/pdb

Classification: HYDROLASE
Organism(s): Oryctolagus cuniculus
Expression System: Komagataella pastoris
Mutation(s): Yes

Deposited: 2017-03-08 Released: 2018-03-14
Deposition Author(s): Labiuk, S.L., Grochulski, P., Sygusch, J.
Funding Organization(s): Medical Research Council (MRC, Canada)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.00 Å
R-Value Free: 0.245
R-Value Work: 0.195
R-Value Observed: 0.199

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.2 of the entry. See complete history.

Literature

Structures of soluble rabbit neprilysin complexed with phosphoramidon or thiorphan.

Labiuk, S.L., Sygusch, J., Grochulski, P.

(2019) Acta Crystallogr F Struct Biol Commun 75: 405-411

PubMed: 31204686 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1107/S2053230X19006046
Primary Citation of Related Structures:
4XBH, 4ZR5, 5V48

PubMed Abstract:
Neutral endopeptidase (neprilysin; NEP) is a proteinase that cleaves a wide variety of peptides and has been implicated in Alzheimer's disease, cardiovascular conditions, arthritis and other inflammatory diseases. The structure of the soluble extracellular domain (residues 55-750) of rabbit neprilysin was solved both in its native form at 2.1 Å resolution, and bound to the inhibitors phosphoramidon and thiorphan at 2.8 and 3.0 Å resolution, respectively. Consistent with the extracellular domain of human neprilysin, the structure reveals a large central cavity which contains the active site and the location for inhibitor binding.

Organizational Affiliation

Canadian Light Source, 44 Innovation Boulevard, Saskatoon, SK S7N 2V3, Canada.

Macromolecule Content

Total Structure Weight: 161.96 kDa
Atom Count: 12,108
Modelled Residue Count: 1,392
Deposited Residue Count: 1,392
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Neprilysin	A, B	696	Oryctolagus cuniculus	Mutation(s): 2 Gene Names: MME EC: 3.4.24.11
UniProt
Find proteins for P08049 (Oryctolagus cuniculus) Explore P08049 Go to UniProtKB: P08049
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08049
Glycosylation
Glycosylation Sites: 4	Glycosylation Focus chain A Focus chain B
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C, D, E, F	2		N-Glycosylation	Interactions Focus chain C Focus chain D Focus chain E Focus chain F Interactions & Density Focus chain C Focus chain D Focus chain E Focus chain F
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
TIO Query on TIO Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain L [auth B] MOL2 format, chain H [auth A] MOL2 format, chain L [auth B] mmCIF format, chain H [auth A] mmCIF format, chain L [auth B]	H [auth A], L [auth B]	(2-MERCAPTOMETHYL-3-PHENYL-PROPIONYL)-GLYCINE C₁₂ H₁₅ N O₃ S LJJKNPQAGWVLDQ-SNVBAGLBSA-N		Interactions Focus chain H [auth A] Focus chain L [auth B] Interactions & Density Focus chain H [auth A] Focus chain L [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain M [auth B] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain M [auth B] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain M [auth B]	I [auth A], J [auth A], M [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Interactions & Density Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain K [auth B] MOL2 format, chain G [auth A] MOL2 format, chain K [auth B] mmCIF format, chain G [auth A] mmCIF format, chain K [auth B]	G [auth A], K [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain K [auth B] Interactions & Density Focus chain G [auth A] Focus chain K [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
TIO	BindingDB: 5V48	Ki: min: 1.5, max: 40 (nM) from 9 assay(s)
TIO	BindingDB: 5V48	IC50: min: 1, max: 40 (nM) from 24 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.00 Å
R-Value Free: 0.245
R-Value Work: 0.195
R-Value Observed: 0.199
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 68.994	α = 90
b = 108.446	β = 90
c = 211.887	γ = 90

Software Package:

Software Name	Purpose
DENZO	data collection
SCALEPACK	data scaling
PHENIX	refinement
PDB_EXTRACT	data extraction
DENZO	data reduction
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2018-03-14

Deposition Author(s):

Labiuk, S.L.

Grochulski, P.

Sygusch, J.

Funding Organization	Location	Grant Number
Medical Research Council (MRC, Canada)	Canada	--

Revision History (Full details and data files)

Version 1.0: 2018-03-14
Type: Initial release
Version 1.1: 2019-06-26
Changes: Data collection, Database references
Version 1.2: 2019-11-13
Changes: Database references
Version 1.3: 2020-01-08
Changes: Author supporting evidence
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2023-10-04
Changes: Data collection, Database references, Refinement description, Structure summary
Version 2.2: 2024-10-23
Changes: Structure summary