PDB-8a3q: Human Plasma Kallekrein in complex with 14W

ID or keywords:

Entry

Database: PDB / ID: 8a3q

Title

Human Plasma Kallekrein in complex with 14W

Components

Plasma kallikrein

Keywords

HYDROLASE / Inhibitor /

Complex / serine-like protease

Function / homology

Function and homology information

plasma kallikrein / Factor XII activation / Defective SERPING1 causes hereditary angioedema / positive regulation of fibrinolysis / zymogen activation / plasminogen activation / Defective factor XII causes hereditary angioedema / Activation of Matrix Metalloproteinases /

fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.801 Å

Authors

McEwan, P.A.

Funding support

United Kingdom, 1items

Citation

Journal: J.Med.Chem. / Year: 2022
Title: Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.
Authors: Davie, R.L. / Edwards, H.J. / Evans, D.M. / Hodgson, S.T. / Stocks, M.J. / Smith, A.J. / Rushbrooke, L.J. / Pethen, S.J. / Roe, M.B. / Clark, D.E. / McEwan, P.A. / Hampton, S.L.

History

Deposition	Jun 8, 2022	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Nov 2, 2022	Provider: repository / Type: Initial release
Revision 1.1	Nov 9, 2022	Group: Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2	Jan 31, 2024	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

-
Download

PDBx/mmCIF format	8a3q.cif.gz	118.3 KB	Display	PDBx/mmCIF format
PDB format	pdb8a3q.ent.gz	88.3 KB	Display	PDB format
PDBx/mmJSON format	8a3q.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

-
Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/a3/8a3q ftp://data.pdbj.org/pub/pdb/validation_reports/a3/8a3q	HTTPS FTP

-
Related structure data

Related structure data	2anwS S: Starting model for refinement
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

-
Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#25 - Jan 2002 Thrombin similarity (2) #83 - Nov 2006 Fibrin similarity (2) #237 - Sep 2019 Nanodiscs and HDL similarity (1) #137 - May 2011 Cytochrome bc1 similarity (1) #191 - Nov 2015 Glutamate-gated Chloride Receptors similarity (1) #75 - Mar 2006 Tissue Factor similarity (1)

Deposited unit

A: Plasma kallikrein

hetero molecules

29.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	63.438, 79.018, 49.875
Angle α, β, γ (deg.)	90, 90, 90
Int Tables number	18
Space group name H-M	P2₁2₁2

#1: Protein

Plasma kallikrein /

/ Fletcher factor / Kininogenin / Plasma prekallikrein / PKK

Mass: 29366.217 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: KLKB1, KLK3 / Production host:

Komagataella pastoris (fungus) / Strain (production host): X33 / References: UniProt: P03952,

plasma kallikrein

#2: Chemical

ChemComp-UNL / UNKNOWN LIGAND

Num. of mol.: 1 / Source method: obtained synthetically / Feature type: SUBJECT OF INVESTIGATION

#3: Chemical

ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID /

MES (buffer)

Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₆H₁₃NO₄S / Comment: pH buffer*YM

#4: Sugar

ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE /

N-Acetylglucosamine

Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₈H₁₅NO₆

Identifier	Type	Program
DGlcpNAcb	CONDENSED IUPAC CARBOHYDRATE SYMBOL	GMML 1.0
N-acetyl-b-D-glucopyranosamine	COMMON NAME	GMML 1.0
b-D-GlcpNAc	IUPAC CARBOHYDRATE SYMBOL	PDB-CARE 1.0
GlcNAc	SNFG CARBOHYDRATE SYMBOL	GMML 1.0

#5: Water

ChemComp-HOH / water /

Water

Mass: 18.015 Da / Num. of mol.: 64 / Source method: isolated from a natural source / Formula: H₂O

Has ligand of interest

Y

-
Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

Crystal	Density Matthews: 2.13 Å³/Da / Density % sol: 42.21 %
Crystal grow	Temperature: 291 K / Method: counter-diffusion / pH: 5.5 Details: 25% PEG 6K, 0.10 M MES, pH 6.5, 14 mg/mL protein including 20 mM Benzamidine. 1:1 ratio of protein to mother liquor at 1 + 1 microliters over a 500 microliter reservoir at 18 Celsius PH range: 5 to 6

-
Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

ESRF

/ Beamline: ID23-1 / Wavelength: 0.978563 Å

Detector

Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 15, 2015

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.978563 Å / Relative weight: 1

Reflection

Resolution: 1.801→49.875 Å / Num. obs: 15758 / % possible obs: 86.7 % / Redundancy: 6.28 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC_1/2: 0.999 / CC_1/2 anomalous: -0.182 / R_merge(I) obs: 0.0586 / R_pim(I) all: 0.0257 / R_rim(I) all: 0.0642 / AbsDiff over sigma anomalous: 0.674 / B_aniso tensor eigenvalue 1: 28.1 Å² / B_aniso tensor eigenvalue 2: 48.3 Å² / B_aniso tensor eigenvalue 3: 65.9 Å² / B_aniso tensor eigenvector 1 ortho1: 1 / B_aniso tensor eigenvector 1 ortho2: 0 / B_aniso tensor eigenvector 1 ortho3: 0 / B_aniso tensor eigenvector 2 ortho1: 0 / B_aniso tensor eigenvector 2 ortho2: 1 / B_aniso tensor eigenvector 2 ortho3: 0 / B_aniso tensor eigenvector 3 ortho1: 0 / B_aniso tensor eigenvector 3 ortho2: 0 / B_aniso tensor eigenvector 3 ortho3: 1 / Aniso diffraction limit 1: 1.65 Å / Aniso diffraction limit 2: 1.975 Å / Aniso diffraction limit 3: 2.319 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 14.08 / Num. measured all: 98995 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 85.5 / % possible ellipsoidal: 86.7 / % possible ellipsoidal anomalous: 85.5 / % possible spherical: 66.1 / % possible spherical anomalous: 64.4 / Redundancy anomalous: 3.4 / Signal type: local

Reflection shell

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Mean I/σ(I) obs	Num. measured all	Num. measured obs	Num. unique all	Num. unique obs	CC_1/2	CC_1/2 anomalous	R_pim(I) all	R_rim(I) all	AbsDiff over sigma anomalous	% possible anomalous	% possible ellipsoidal	% possible ellipsoidal anomalous	% possible spherical	% possible spherical anomalous	Redundancy anomalous	% possible all
5.823-49.875	5.76	0.0465	32.39	4537	4537	788	788	0.998	-0.342	0.022	0.0517	0.617	99.1	98.6	99.1	98.6	99.1	3.48	98.6
4.571-5.823	6.01	0.0438	32.23	4733	4733	787	787	0.999	-0.007	0.0191	0.0479	0.631	99.4	99.6	99.4	99.6	99.4	3.37	99.6
3.976-4.571	6.39	0.0434	32.71	5043	5043	789	789	0.999	-0.01	0.0183	0.0472	0.615	100	99.7	100	99.7	100	3.53	99.7
3.596-3.976	5.94	0.045	28.98	4678	4678	788	788	0.998	-0.213	0.0197	0.0492	0.642	98.9	99.7	98.9	99.7	98.9	3.27	99.7
3.328-3.596	6.46	0.0533	26.87	5084	5084	787	787	0.998	-0.276	0.0225	0.058	0.679	99.4	99.2	99.4	99.2	99.4	3.49	99.2
3.127-3.328	6.54	0.0637	22.43	5145	5145	787	787	0.996	-0.06	0.0274	0.0696	0.689	100	99.9	100	99.9	100	3.53	99.9
2.966-3.127	6.27	0.077	17.61	4944	4944	789	789	0.997	-0.144	0.0338	0.0843	0.704	98.8	99.6	98.8	99.6	98.8	3.41	99.6
2.834-2.966	6.25	0.1	14.43	4918	4918	787	787	0.995	-0.147	0.043	0.109	0.712	99.6	99.2	99.6	99.2	99.6	3.33	99.2
2.722-2.834	6.52	0.1162	12.33	5135	5135	788	788	0.995	-0.166	0.0494	0.1265	0.715	99.6	99.6	99.6	99.6	99.6	3.48	99.6
2.624-2.722	6.72	0.1397	11.05	5298	5298	788	788	0.994	-0.126	0.0583	0.1516	0.689	99.1	99.4	99.1	99.4	99.1	3.58	99.4
2.54-2.624	6.79	0.1712	9.53	5357	5357	789	789	0.991	-0.061	0.0705	0.1854	0.68	99.4	99.9	99.4	99.9	99.4	3.62	99.9
2.465-2.54	6.65	0.2132	7.73	5230	5230	787	787	0.984	-0.011	0.0888	0.2313	0.669	99.3	98.9	99.3	98.9	99.3	3.54	98.9
2.396-2.465	6.14	0.2518	6.41	4839	4839	788	788	0.973	-0.02	0.1088	0.275	0.687	95.6	96.6	95.6	96.6	95.6	3.29	96.6
2.329-2.396	6.57	0.2798	6.15	5178	5178	788	788	0.97	0.028	0.1173	0.3038	0.696	88.4	87.1	88.4	87.1	88.4	3.46	87.1
2.265-2.329	6.64	0.2884	5.86	5236	5236	789	789	0.975	-0.067	0.1202	0.3128	0.661	85.3	85.6	85.3	83.9	84	3.49	85.6
2.18-2.265	6.41	0.4038	4.24	5043	5043	787	787	0.941	-0.112	0.1702	0.4391	0.645	61.4	62.1	61.4	54.4	54.2	3.41	62.1
2.12-2.18	6.65	0.4454	3.91	5235	5235	787	787	0.929	-0.007	0.1853	0.4832	0.677	86.1	87.3	86.1	67.6	67.2	3.53	87.3
2.045-2.12	5.92	0.5867	2.74	4668	4668	788	788	0.875	0.039	0.2541	0.6412	0.702	66.5	69.6	66.5	47.4	45.3	3.24	69.6
1.966-2.045	5.86	0.6532	2.41	4621	4621	788	788	0.775	-0.045	0.2898	0.7168	0.669	70	71	70	39.2	38.4	3.14	71
1.801-1.966	5.16	0.9202	1.52	4073	4073	789	789	0.564	-0.01	0.4356	1.0229	0.687	42.2	45.4	42.2	14.6	13.5	2.83	45.4

-
Processing

Software

Name	Version	Classification
autoPROC	1.1.7 20210716	data processing
XDS	Feb 5, 2021	data reduction
Aimless	0.7.4	data scaling
STARANISO	2.3.77	data scaling
BUSTER	2.11.8	refinement
Coot		model building
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 2ANW

2anw

Resolution: 1.801→49.88 Å / Cor.coef. F_o:F_c: 0.921 / Cor.coef. F_o:F_c free: 0.918 / SU R Cruickshank DPI: 0.251 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.255 / SU R_free Blow DPI: 0.202 / SU R_free Cruickshank DPI: 0.202

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2725	786	-	RANDOM
R_work	0.2353	-	-	-
obs	0.2372	15758	66 %	-

Displacement parameters

B_iso mean: 49.74 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-5.3202 Å²	0 Å²	0 Å²
2-	-	-1.7794 Å²	0 Å²
3-	-	-	7.0996 Å²

Refine analyze

Luzzati coordinate error obs: 0.33 Å

Refinement step

Cycle: LAST / Resolution: 1.801→49.88 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	1905	0	62	64	2031

Refine LS restraints

Refine-ID	Type	Dev ideal	Number	Restraint function	Weight
X-RAY DIFFRACTION	t_bond_d	0.008	2027	HARMONIC	2
X-RAY DIFFRACTION	t_angle_deg	1.01	2754	HARMONIC	2
X-RAY DIFFRACTION	t_dihedral_angle_d		697	SINUSOIDAL	2
X-RAY DIFFRACTION	t_gen_planes		348	HARMONIC	5
X-RAY DIFFRACTION	t_it		2027	HARMONIC	10
X-RAY DIFFRACTION	t_chiral_improper_torsion		256	SEMIHARMONIC	5
X-RAY DIFFRACTION	t_ideal_dist_contact		1618	SEMIHARMONIC	4
X-RAY DIFFRACTION	t_omega_torsion	3.46
X-RAY DIFFRACTION	t_other_torsion	18.08

LS refinement shell

Resolution: 1.801→1.92 Å

	R_factor	Num. reflection	% reflection
R_free	0.3124	15	-
R_work	0.3085	-	-
obs	-	-	10.17 %

Refinement TLS params.

Origin x: 15.8537 Å / Origin y: 14.2141 Å / Origin z: 10.7599 Å

	11	12	13	21	22	23	31	32	33
T	-0.087 Å²	0.0696 Å²	0.0783 Å²	-	-0.0122 Å²	0.1208 Å²	-	-	0.0868 Å²
L	6.3147 °²	-2.1269 °²	-0.4183 °²	-	1.7913 °²	0.916 °²	-	-	1.0705 °²
S	-0.5368 Å °	0.0038 Å °	0.1127 Å °	0.0038 Å °	0.3111 Å °	-0.0759 Å °	0.1127 Å °	-0.0759 Å °	0.2257 Å °

Refinement TLS group

Selection details: { A|16 - A|248 }

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

Version 3 of the EMDB header file is now the official format.
The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

+
Jul 12, 2017. Major update of PDB

-
Yorodumi

Thousand views of thousand structures

Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

-
Movie

-
Structure viewers

+
Viewer log

-
This page

-
This web site

-
Options

+
Open data

-
Basic information

-
Structure visualization

-
Downloads & links

-
Download

-
Validation report

-
Related structure data

-
Links

-
Assembly

-
Components

-
Experimental details

-
Experiment

-
Sample preparation

-
Data collection

-
Processing

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

-
Aug 12, 2020. Covid-19 info

+
Mar 5, 2020. Novel coronavirus structure data

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

+
Jul 12, 2017. Major update of PDB

-
Yorodumi

-Movie

-Structure viewers

+Viewer log

-This page

-This web site

-Options

+Open data

-Basic information

-Structure visualization

-Downloads & links

-Download

-Validation report

-Related structure data

-Links

-Assembly

-Components

-Experimental details

-Experiment

-Sample preparation

-Data collection

-Processing

+About Yorodumi

-News

-Feb 9, 2022. New format data for meta-information of EMDB entries

-Aug 12, 2020. Covid-19 info

+Mar 5, 2020. Novel coronavirus structure data

+Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

+Jul 12, 2017. Major update of PDB

-Yorodumi

-
Movie

-
Structure viewers

+
Viewer log

-
This page

-
This web site

-
Options

+
Open data

-
Basic information

-
Structure visualization

-
Downloads & links

-
Download

-
Validation report

-
Related structure data

-
Links

-
Assembly

-
Components

-
Experimental details

-
Experiment

-
Sample preparation

-
Data collection

-
Processing

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

-
Aug 12, 2020. Covid-19 info

+
Mar 5, 2020. Novel coronavirus structure data

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

+
Jul 12, 2017. Major update of PDB

-
Yorodumi