Target Information

Target General Information

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Target ID

T85944 (Former ID: TTDR00865)

Target Name

Pseudomonas UDP-3-O-acyl-GlcNAc deacetylase (Pseudo lpxC)

Synonyms

Pseudo UDP-3-O-acyl-GlcNAc deacetylase; EnvA protein

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Gene Name

Pseudo lpxC

Target Type

Preclinical target

[1]

Disease

[+] 2 Target-related Diseases

Pneumonia [ICD-11: CA40]

Gram-negative bacterial infection [ICD-11: 1F41-1G40]

Function

Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.

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BioChemical Class

Carbon-nitrogen hydrolase

UniProt ID

LPXC_PSEAE

EC Number

EC 3.5.1.108

Sequence

MIKQRTLKNIIRATGVGLHSGEKVYLTLKPAPVDTGIVFCRTDLDPVVEIPARAENVGET
TMSTTLVKGDVKVDTVEHLLSAMAGLGIDNAYVELSASEVPIMDGSAGPFVFLIQSAGLQ
EQEAAKKFIRIKREVSVEEGDKRAVFVPFDGFKVSFEIDFDHPVFRGRTQQASVDFSSTS
FVKEVSRARTFGFMRDIEYLRSQNLALGGSVENAIVVDENRVLNEDGLRYEDEFVKHKIL
DAIGDLYLLGNSLIGEFRGFKSGHALNNQLLRTLIADKDAWEVVTFEDARTAPISYMRPA
AAV

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3D Structure

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PDB

Drugs and Modes of Action

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Preclinical Drug(s)

[+] 1 Preclinical Drugs

LpxC-1

Drug Info

Preclinical

Acinetobacter baumannii infection

[2]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

RC-01

Drug Info

Terminated

Gram-negative bacterial infection

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 9 Inhibitor drugs

LpxC-1

Drug Info

[2]

RC-01

Drug Info

[3]

3-(heptyloxy)benzoic acid

Drug Info

[4]

BB-78484

Drug Info

[5]

BB-78485

Drug Info

[5]

Cacodylate Ion

Drug Info

[1]

MYRISTIC ACID

Drug Info

[4]

Palmitoleic Acid

Drug Info

[1]

Tu-514

Drug Info

[1]

Drug Binding Sites of Target

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Ligand Name: ACHN-975

Ligand Info

Structure Description

Co-Crystal structure of P. aeruginosa LpxC-achn975 complex

PDB:6MOO

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[6]

PDB Sequence

HHEGAGTIKQ

⁴

RTLKNIIRAT

¹⁴

GVGLHSGEKV

²⁴

YLTLKPAPVD

³⁴

TGIVFSRTDL

⁴⁴

DPVVEIPARA

⁵⁴

ENVGETTMST

⁶⁴

TLVKGDVKVD

⁷⁴

TVEHLLSAMA

⁸⁴

GLGIDNAYVE

⁹⁴

LSASEVPIMD

¹⁰⁴

GSAGPFVFLI

¹¹⁴

QSAGLQEQEA

¹²⁴

AKKFIRIKRE

¹³⁴

VSVEEGDKRA

¹⁴⁴

VFVPFDGFKV

¹⁵⁴

SFEIDFDHPV

¹⁶⁴

FQQASVDFSS

¹⁷⁸

TSFVKEVSRA

¹⁸⁸

RTFGFMRDIE

¹⁹⁸

YLRSQNLALG

²⁰⁸

GSVENAIVVD

²¹⁸

ENRVLNEDGL

²²⁸

RYEDEFVKHK

²³⁸

ILDAIGDLYL

²⁴⁸

LGNSLIGEFR

²⁵⁸

GFKSGHALNN

²⁶⁸

QLLRTLIADK

²⁷⁸

DAWEVVTFED

²⁸⁸

ARTAPISYMR

²⁹⁸

Residue

Distance (Å)

LEU18

3.871

HIS19

4.225

MET62

4.010

SER63

4.948

GLU77

2.274

HIS78

3.119

THR190

2.308

PHE191

3.150

GLY192

4.088

MET194

4.006

ILE197

3.753

LEU200

4.533

Residue

Distance (Å)

ARG201

3.839

ALA206

3.774

GLY209

3.138

SER210

3.575

VAL211

3.557

ALA214

3.939

VAL216

4.207

HIS237

2.942

LYS238

3.943

ASP241

3.105

HIS264

3.233

Ligand Name: BB-78485

Ligand Info

Structure Description

Crystal Structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor

PDB:2VES

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[7]

PDB Sequence

MIKQRTLKNI

¹⁰

IRATGVGLHS

²⁰

GEKVYLTLKP

³⁰

APVDTGIVFS

⁴⁰

RTDLDPVVEI

⁵⁰

PARAENVGET

⁶⁰

TMSTTLVKGD

⁷⁰

VKVDTVEHLL

⁸⁰

SAMAGLGIDN

⁹⁰

AYVELSASEV

¹⁰⁰

PIMDGSAGPF

¹¹⁰

VFLIQSAGLQ

¹²⁰

EQEAAKKFIR

¹³⁰

IKREVSVEEG

¹⁴⁰

DKRAVFVPFD

¹⁵⁰

GFKVSFEIDF

¹⁶⁰

DHPVFRGRTQ

¹⁷⁰

QASVDFSSTS

¹⁸⁰

FVKEVSRART

¹⁹⁰

FGFMRDIEYL

²⁰⁰

RSQNLALGGS

²¹⁰

VENAIVVDEN

²²⁰

RVLNEDGLRY

²³⁰

EDEFVKHKIL

²⁴⁰

DAIGDLYLLG

²⁵⁰

NSLIGEFRGF

²⁶⁰

KSGHALNNQL

²⁷⁰

LRTLIADKDA

²⁸⁰

WEVVTFEDAR

²⁹⁰

TAPI

Residue

Distance (Å)

LEU18

3.149

MET62

2.985

SER63

3.705

THR75

3.941

GLU77

2.512

HIS78

3.243

ILE102

3.846

THR190

2.672

PHE191

3.257

GLY192

3.456

PHE193

3.830

Residue

Distance (Å)

ASP196

3.857

ILE197

3.681

LEU200

3.985

ALA206

4.188

GLY209

3.547

SER210

3.829

ASN213

3.301

ALA214

3.554

HIS237

2.951

ASP241

2.953

HIS264

2.912

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Similarity Proteins

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Similarity Proteins

There is no similarity protein (E value < 0.005) for this target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Lipopolysaccharide biosynthesis

Metabolic pathways

Target-Related Models and Studies

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Target QSAR Model

References

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REF 1

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 2

Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov. 2017 Jul;16(7):457-471.

REF 3

The global preclinical antibacterial pipeline. Nat Rev Microbiol. 2020 May;18(5):275-285.

REF 4

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 5

Antibacterial activities and characterization of novel inhibitors of LpxC. Antimicrob Agents Chemother. 2002 Jun;46(6):1793-9.

REF 6

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety. ChemMedChem. 2019 Aug 20;14(16):1560-1572.

REF 7

Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor. Protein Sci. 2008 Mar;17(3):450-7.

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