3V6O | pdb_00003v6o

Leptin Receptor-antibody complex

PDB DOI: https://doi.org/10.2210/pdb3V6O/pdb

Classification: IMMUNE SYSTEM
Organism(s): Homo sapiens, Mus musculus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2011-12-20 Released: 2012-03-14
Deposition Author(s): Carpenter, B., Hemsworth, G.R., Ross, R.J., Artymiuk, P.J.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.95 Å
R-Value Free:
0.213 (Depositor), 0.220 (DCC)
R-Value Work:
0.171 (Depositor), 0.180 (DCC)
R-Value Observed:
0.173 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody.

Carpenter, B., Hemsworth, G.R., Wu, Z., Maamra, M., Strasburger, C.J., Ross, R.J., Artymiuk, P.J.

(2012) Structure 20: 487-497

PubMed: 22405007 Search on PubMed
DOI: https://doi.org/10.1016/j.str.2012.01.019
Primary Citation of Related Structures:
3V6O, 3VG0

PubMed Abstract:
Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR. We describe the structure of the LBD-9F8 Fab complex and the conformational changes in 9F8 associated with LBD binding. A molecular model of the putative leptin-LBD complex reveals that 9F8 Fab blocks leptin binding through only a small (10%) overlap in their binding sites, and that leptin binding is likely to involve an induced fit mechanism. This crystal structure of the leptin-binding domain of the obesity receptor will facilitate the design of therapeutics to modulate leptin signaling.

Organizational Affiliation

Academic Unit of Diabetes, Endocrinology and Reproduction, Department of Human Metabolism, University of Sheffield, Sheffield S10 2JF, UK.

Macromolecule Content

Total Structure Weight: 144.46 kDa
Atom Count: 10,514
Modelled Residue Count: 1,225
Deposited Residue Count: 1,284
Unique protein chains: 3

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Leptin receptor	A, B	206	Homo sapiens	Mutation(s): 0 Gene Names: DB, LEPR, OBR
UniProt & NIH Common Fund Data Resources
Find proteins for P48357 (Homo sapiens) Explore P48357 Go to UniProtKB: P48357
PHAROS: P48357 GTEx: ENSG00000116678
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P48357
Sequence Annotations Expand
Reference Sequence LOADING

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Monoclonal antibody 9F8 fab fragment Heavy chain	C, D	221	Mus musculus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence LOADING

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Monoclonal antibody 9F8 fab fragment Light chain	E, F	215	Mus musculus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain F
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain MA [auth F] MOL2 format, chain MA [auth F] mmCIF format, chain MA [auth F]	MA [auth F]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain MA [auth F] Interactions & Density Focus chain MA [auth F]
CYS Query on CYS Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain P [auth B] MOL2 format, chain G [auth A] MOL2 format, chain P [auth B] mmCIF format, chain G [auth A] mmCIF format, chain P [auth B]	G [auth A], P [auth B]	CYSTEINE C₃ H₇ N O₂ S XUJNEKJLAYXESH-REOHCLBHSA-N		Interactions Focus chain G [auth A] Focus chain P [auth B] Interactions & Density Focus chain G [auth A] Focus chain P [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain BA [auth D] SDF format, chain CA [auth D] SDF format, chain DA [auth D] SDF format, chain EA [auth D] SDF format, chain FA [auth D] SDF format, chain H [auth A] SDF format, chain HA [auth D] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain JA [auth E] SDF format, chain KA [auth E] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain O [auth A] SDF format, chain QA [auth F] SDF format, chain R [auth B] SDF format, chain RA [auth F] SDF format, chain S [auth B] SDF format, chain SA [auth F] SDF format, chain T [auth B] SDF format, chain TA [auth F] SDF format, chain U [auth B] SDF format, chain X [auth C] SDF format, chain Y [auth C] SDF format, chain GA [auth D] SDF format, chain K [auth A] SDF format, chain LA [auth E] SDF format, chain PA [auth F] SDF format, chain Q [auth B] SDF format, chain UA [auth F] MOL2 format, chain BA [auth D] MOL2 format, chain CA [auth D] MOL2 format, chain DA [auth D] MOL2 format, chain EA [auth D] MOL2 format, chain FA [auth D] MOL2 format, chain H [auth A] MOL2 format, chain HA [auth D] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain JA [auth E] MOL2 format, chain KA [auth E] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain O [auth A] MOL2 format, chain QA [auth F] MOL2 format, chain R [auth B] MOL2 format, chain RA [auth F] MOL2 format, chain S [auth B] MOL2 format, chain SA [auth F] MOL2 format, chain T [auth B] MOL2 format, chain TA [auth F] MOL2 format, chain U [auth B] MOL2 format, chain X [auth C] MOL2 format, chain Y [auth C] MOL2 format, chain GA [auth D] MOL2 format, chain K [auth A] MOL2 format, chain LA [auth E] MOL2 format, chain PA [auth F] MOL2 format, chain Q [auth B] MOL2 format, chain UA [auth F] mmCIF format, chain BA [auth D] mmCIF format, chain CA [auth D] mmCIF format, chain DA [auth D] mmCIF format, chain EA [auth D] mmCIF format, chain FA [auth D] mmCIF format, chain H [auth A] mmCIF format, chain HA [auth D] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain JA [auth E] mmCIF format, chain KA [auth E] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain O [auth A] mmCIF format, chain QA [auth F] mmCIF format, chain R [auth B] mmCIF format, chain RA [auth F] mmCIF format, chain S [auth B] mmCIF format, chain SA [auth F] mmCIF format, chain T [auth B] mmCIF format, chain TA [auth F] mmCIF format, chain U [auth B] mmCIF format, chain X [auth C] mmCIF format, chain Y [auth C] mmCIF format, chain GA [auth D] mmCIF format, chain K [auth A] mmCIF format, chain LA [auth E] mmCIF format, chain PA [auth F] mmCIF format, chain Q [auth B] mmCIF format, chain UA [auth F]	BA [auth D] CA [auth D] DA [auth D] EA [auth D] FA [auth D] BA [auth D], CA [auth D], DA [auth D], EA [auth D], FA [auth D], GA [auth D], H [auth A], HA [auth D], I [auth A], J [auth A], JA [auth E], K [auth A], KA [auth E], L [auth A], LA [auth E], M [auth A], N [auth A], O [auth A], PA [auth F], Q [auth B], QA [auth F], R [auth B], RA [auth F], S [auth B], SA [auth F], T [auth B], TA [auth F], U [auth B], UA [auth F], X [auth C], Y [auth C]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain BA [auth D] Focus chain CA [auth D] Focus chain DA [auth D] Focus chain EA [auth D] Focus chain FA [auth D] Focus chain GA [auth D] Focus chain H [auth A] Focus chain HA [auth D] Focus chain I [auth A] Focus chain J [auth A] Focus chain JA [auth E] Focus chain K [auth A] Focus chain KA [auth E] Focus chain L [auth A] Focus chain LA [auth E] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain PA [auth F] Focus chain Q [auth B] Focus chain QA [auth F] Focus chain R [auth B] Focus chain RA [auth F] Focus chain S [auth B] Focus chain SA [auth F] Focus chain T [auth B] Focus chain TA [auth F] Focus chain U [auth B] Focus chain UA [auth F] Focus chain X [auth C] Focus chain Y [auth C] Interactions & Density Focus chain BA [auth D] Focus chain CA [auth D] Focus chain DA [auth D] Focus chain EA [auth D] Focus chain FA [auth D] Focus chain GA [auth D] Focus chain H [auth A] Focus chain HA [auth D] Focus chain I [auth A] Focus chain J [auth A] Focus chain JA [auth E] Focus chain K [auth A] Focus chain KA [auth E] Focus chain L [auth A] Focus chain LA [auth E] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain PA [auth F] Focus chain Q [auth B] Focus chain QA [auth F] Focus chain R [auth B] Focus chain RA [auth F] Focus chain S [auth B] Focus chain SA [auth F] Focus chain T [auth B] Focus chain TA [auth F] Focus chain U [auth B] Focus chain UA [auth F] Focus chain X [auth C] Focus chain Y [auth C]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain IA [auth E] SDF format, chain NA [auth F] SDF format, chain OA [auth F] SDF format, chain V [auth C] SDF format, chain W [auth C] SDF format, chain AA [auth D] MOL2 format, chain IA [auth E] MOL2 format, chain NA [auth F] MOL2 format, chain OA [auth F] MOL2 format, chain V [auth C] MOL2 format, chain W [auth C] MOL2 format, chain AA [auth D] mmCIF format, chain IA [auth E] mmCIF format, chain NA [auth F] mmCIF format, chain OA [auth F] mmCIF format, chain V [auth C] mmCIF format, chain W [auth C] mmCIF format, chain AA [auth D]	AA [auth D] IA [auth E] NA [auth F] OA [auth F] V [auth C] AA [auth D], IA [auth E], NA [auth F], OA [auth F], V [auth C], W [auth C]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain AA [auth D] Focus chain IA [auth E] Focus chain NA [auth F] Focus chain OA [auth F] Focus chain V [auth C] Focus chain W [auth C] Interactions & Density Focus chain AA [auth D] Focus chain IA [auth E] Focus chain NA [auth F] Focus chain OA [auth F] Focus chain V [auth C] Focus chain W [auth C]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain Z [auth C] MOL2 format, chain Z [auth C] mmCIF format, chain Z [auth C]	Z [auth C]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain Z [auth C] Interactions & Density Focus chain Z [auth C]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.95 Å
R-Value Free: 0.213 (Depositor), 0.220 (DCC)
R-Value Work: 0.171 (Depositor), 0.180 (DCC)
R-Value Observed: 0.173 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 89.814	α = 90
b = 118.829	β = 90
c = 171.281	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
PDB_EXTRACT	data extraction
ADSC	data collection
MOSFLM	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-03-14

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-03-14
Type: Initial release
Version 1.1: 2012-04-25
Changes: Database references
Version 1.2: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Database references, Derived calculations, Structure summary
Version 1.3: 2023-12-27
Changes: Data collection, Database references, Derived calculations, Structure summary
Version 1.4: 2024-10-16
Changes: Structure summary