5JMY

NEPRILYSIN COMPLEXED WITH LBQ657

PDB DOI: https://doi.org/10.2210/pdb5JMY/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2016-04-29 Released: 2016-06-15
Deposition Author(s): Schiering, N., Wiesmann, C.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.228
R-Value Work: 0.186
R-Value Observed: 0.188

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

Structure of neprilysin in complex with the active metabolite of sacubitril.

Schiering, N., D'Arcy, A., Villard, F., Ramage, P., Logel, C., Cumin, F., Ksander, G.M., Wiesmann, C., Karki, R.G., Mogi, M.

(2016) Sci Rep 6: 27909-27909

PubMed: 27302413 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/srep27909
Primary Citation of Related Structures:
5JMY

PubMed Abstract:
Sacubitril is an ethyl ester prodrug of LBQ657, the active neprilysin (NEP) inhibitor, and a component of LCZ696 (sacubitril/valsartan). We report herein the three-dimensional structure of LBQ657 in complex with human NEP at 2 Å resolution. The crystal structure unravels the binding mode of the compound occupying the S1, S1' and S2' sub-pockets of the active site, consistent with a competitive inhibition mode. An induced fit conformational change upon binding of the P1'-biphenyl moiety of the inhibitor suggests an explanation for its selectivity against structurally homologous zinc metallopeptidases.

Organizational Affiliation

Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.

Macromolecule Content

Total Structure Weight: 162.59 kDa
Atom Count: 12,295
Modelled Residue Count: 1,392
Deposited Residue Count: 1,396
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	698	Homo sapiens	Mutation(s): 0 Gene Names: MME, EPN EC: 3.4.24.11
UniProt & NIH Common Fund Data Resources
Find proteins for P08473 (Homo sapiens) Explore P08473 Go to UniProtKB: P08473
PHAROS: P08473 GTEx: ENSG00000196549
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08473
Glycosylation
Glycosylation Sites: 4	Glycosylation Focus chain A Focus chain B	Go to GlyGen: P08473-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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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	2		N-Glycosylation	Interactions Focus chain C Focus chain D Interactions & Density Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
6LD Query on 6LD Download Ideal Coordinates CCD File SDF format, chain N [auth B] SDF format, chain I [auth A] MOL2 format, chain N [auth B] MOL2 format, chain I [auth A] mmCIF format, chain N [auth B] mmCIF format, chain I [auth A]	I [auth A], N [auth B]	Sacubitrilat C₂₂ H₂₅ N O₅ DOBNVUFHFMVMDB-BEFAXECRSA-N		Interactions Focus chain I [auth A] Focus chain N [auth B] Interactions & Density Focus chain I [auth A] Focus chain N [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain J [auth B] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain K [auth B] SDF format, chain L [auth B] MOL2 format, chain J [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] mmCIF format, chain J [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain K [auth B] mmCIF format, chain L [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]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-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] 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]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain M [auth B] MOL2 format, chain H [auth A] MOL2 format, chain M [auth B] mmCIF format, chain H [auth A] mmCIF format, chain M [auth B]	H [auth A], M [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain M [auth B] Interactions & Density Focus chain H [auth A] Focus chain M [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
6LD	BindingDB: 5JMY	Ki: 6.31 (nM) from 1 assay(s)
6LD	BindingDB: 5JMY	IC50: min: 5, max: 190 (nM) from 5 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.228
R-Value Work: 0.186
R-Value Observed: 0.188
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 59.737	α = 90
b = 109.139	β = 90
c = 248.003	γ = 90

Software Package:

Software Name	Purpose
XDS	data reduction
XSCALE	data scaling
PHASER	phasing
BUSTER	refinement

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-06-15

Deposition Author(s):

Schiering, N.

Wiesmann, C.

Revision History (Full details and data files)

Version 1.0: 2016-06-15
Type: Initial release
Version 1.1: 2016-06-29
Changes: Database references
Version 1.2: 2019-04-24
Changes: Data collection, Source and taxonomy
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2024-01-10
Changes: Data collection, Database references, Refinement description, Structure summary
Version 2.2: 2024-11-06
Changes: Structure summary